WO2010014611A1 - Cycloalkylidene and heterocycloalkylidene histone deacetylase inhibitor compounds - Google Patents

Cycloalkylidene and heterocycloalkylidene histone deacetylase inhibitor compounds Download PDF

Info

Publication number
WO2010014611A1
WO2010014611A1 PCT/US2009/051964 US2009051964W WO2010014611A1 WO 2010014611 A1 WO2010014611 A1 WO 2010014611A1 US 2009051964 W US2009051964 W US 2009051964W WO 2010014611 A1 WO2010014611 A1 WO 2010014611A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzamide
pyridin
thiazol
cyclopropyl
alkyl
Prior art date
Application number
PCT/US2009/051964
Other languages
French (fr)
Inventor
Lawrence S. Melvin
Michael Graupe
Chandrasekar Venkataramani
Original Assignee
Gilead Colorado, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Colorado, Inc. filed Critical Gilead Colorado, Inc.
Priority to NZ590747A priority Critical patent/NZ590747A/en
Priority to CN2009801320714A priority patent/CN102123987A/en
Priority to MX2011001090A priority patent/MX2011001090A/en
Priority to AU2009276699A priority patent/AU2009276699A1/en
Priority to BRPI0916713A priority patent/BRPI0916713A2/en
Priority to CA2731323A priority patent/CA2731323A1/en
Priority to EP09790886A priority patent/EP2326622A1/en
Priority to JP2011521247A priority patent/JP2011529504A/en
Publication of WO2010014611A1 publication Critical patent/WO2010014611A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention generally relates to a compound having enzyme inhibitory activity, pharmaceutical compositions comprising the compound, and methods useful for treating diseases.
  • Histones are protein components making up chromatin in association with DNA.
  • Histones are subject to covalent modifications of various enzymes such as, for example, histone deacetylase (HDAC), histone methyltransferase (HMT) and histone acetyl transferase (HAT). Covalent modifications of core histones influence protein-protein interaction and protein access to DNA.
  • HDAC histone deacetylase
  • HMT histone methyltransferase
  • HAT histone acetyl transferase
  • HDACs catalyze deacetylation of lysine residues on histones and other proteins. It is known that low levels of histone-acetylation are associated with repression of gene expression. Therefore, abnormal HDAC activities could destroy the delicate balance in cell regulation.
  • the HDACs belong to four structurally and functionally different phylogenetic classes: class I (HDAC-I, -2, -3, and -8) compounds are closely related to yeast RPD3; class Ha (HDAC-4, -5, - 7, and -9) and class lib (HDAC-6 and -10) share domains with yeast HDAC-I; class IV, recently described (comprising HDAC-Il), exhibits properties of both class I and class II HDACs.
  • HDACs are zinc dependent proteases.
  • Class III HDACs have been identified on the basis of sequence similarity with Sir2, a yeast transcription repressor, and require the cofactor NAD + for their deacetylase function. See, for example, Marielle Paris et al., Histone Deacetylase Inhibitors: From Bench to Clinic, JOURNAL OF MEDICINAL CHEMISTRY 51(11): 3330 - 3330 (2008).
  • HDAC inhibitor can provide therapeutic benefits to a broad range of patients. Due to the therapeutic significance, various types of HDAC inhibitors Attorney Docket No. 8493-000092/WO/POA
  • WO 2005/092899 mentions a series of compounds useful for inhibiting HDAC enzymatic activity where the compounds are amino or hydroxyl substituted aniline derivatives attached to various cyclic groups.
  • a compound having HDAC inhibitory activity in various embodiments, a composition comprising the compound, and a method useful to treat diseases arising from abnormal cell proliferation or differentiation are provided.
  • the compound is of Formula (I) or a pharmaceutically acceptable salt thereof:
  • Cy 1 is cycloalkylidene or heterocycloalkylidene; Cy 2 is cycloalkyl, aryl or heterocyclyl; Ar is aryl or heteroaryl; m is an integer from 0 to the maximum number of substitutable positions on Ar; n is an integer from 0 to the maximum number of substitutable positions on Cy 1 ; p is an integer equal to the number of substitutable positions on Cy , wherein a substitutable position is one that, based on the valence of the ring atom occupying the position, can contain H or other substituent. Carbon ring atoms are substitutable, while O and S ring atoms are not substitutable. N ring atoms are substitutable or not, depending on valence. Further, the ring position of Cy 2 occupied by Cy 1 is not substitutble; Attorney Docket No. 8493-000092/WO/POA
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH and aryl or heteroaryl is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; each R 2 is independently selected from the group consisting of hydroxyl, oxo, halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, amino, carboxyl, carbamoyl,
  • R 4 is optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible, or when p is 2 or greater, two R 4 groups together can form a 5- or 6-membered cyclic moiety to make a fused ring with Cy 2 ring, wherein the cyclic moiety can contain one or more heteroatoms selected from ⁇ , O and S and the fused ring is optionally substituted by one or more R 5 where such an optional substitution is chemically feasible; each R 5 is independently selected from halo, nitro, cyano, hydroxyl, oxo, hydroxy(Ci_io alkyl), amino(Ci-io alkyl), haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, Ci_i 0 alkyl, C 2 -io alkenyl, C 2 -io alkynyl, Ci_io alkoxy, hydroxy(
  • A, B and D are independently selected from halo, nitro, cyano, hydroxyl, oxo, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkanoyl, C 1-10 alkanoyloxy, N-(C 1-10 alkyl)amino, N,N-(C 1-10 alkyl) 2 amino, C 1-10 alkanoylamino, N-(C 1-10 alkyl)carbamoyl, N, N- (C 1-10 alkyl) 2 carbamoyl, C 1-10 alkyl-S(O) a wherein a is 0, 1 or 2, C 1-10 alkoxycarbonyl, N- (Ci-io alkyl)sulphamoyl
  • compositions comprise an HDAC-inhibitory effective amount of one or more compounds described herein and a pharmaceutically-acceptable carrier.
  • Methods of inhibiting or treating diseases arising from abnormal cell proliferation and differentiation comprise administering to a subject a therapeutically effective amount of one or more compounds described herein.
  • Other methods involve co-therapies by administering one or more of the compounds together with other anti-cancer agents.
  • alkenyl refers to a straight or branched hydrocarbyl group with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond. In an embodiment, alkenyl has from 2 to 12 carbon atoms. In some embodiments, alkenyl is a C 2 -Ci O alkenyl group or a C 2 -C 6 alkenyl group.
  • alkanoyl is the group RC(O)-; “alkanoyloxy” is RC(O)O-; and “alkanoylamino” is RC(O)NR'-; where R is an alkyl group as defined herein, and R' is H or alkyl. In various embodiments, R is a C 1 -C 1O alkyl group or a Ci-C 6 alkyl group.
  • Alkoxy is RO- where R is alkyl.
  • alkoxy groups include methoxy, ethoxy and propoxy.
  • Alkoxyalkyl refers to an alkyl moiety substituted with an alkoxy group. Examples of alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl and ethoxyethyl.
  • Alkoxycarbonyl is ROC(O)-, where R is an alkyl group as defined herein. In various embodiments, R is a C 1 -C 1 O alkyl group or a Ci-C 6 alkyl group.
  • alkyl refers to a straight or branched chain saturated hydrocarbyl group. In an embodiment, alkyl has from 1 to 12 carbon atoms. In some embodiments, alkyl is a C 1 -C 1O alkyl group or a C 1 -C 6 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Attorney Docket No. 8493-000092/WO/POA
  • Alkylamino refers to an amino group substituted with one or more alkyl groups.
  • 'W-(alkyl)amino is RNH- and 'W,N-(alkyl) 2 amino" is R 2 N-, where the R groups are alkyl as defined herein and are the same or different.
  • R is a C 1 -C 1O alkyl group or a Ci-C 6 alkyl group.
  • alkylamino groups include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, and methylethylamno.
  • Alkylaminoalkyl refers to an alkyl moiety substituted with an alkylamino group, wherein alkylamino is as defined herein.
  • alkylaminoakyl groups include methylaminomethyl and ethylaminomethyl.
  • Alkynyl refers to a straight or branched carbon-chain group with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. In an embodiment, alkynyl has from 2 to 12 carbon atoms. In some embodiments, alkynyl is a C 2 -Ci O alkynyl group or a C 2 -C 6 alkynyl group. Examples of alkynyl groups include acetylenic (-C ⁇ CH) and propargyl (-CH 2 C ⁇ CH).
  • Aryl refers to a monocyclic, bicyclic or tricyclic carbon ring system of up to 7 atoms in each ring, wherein at least one ring is aromatic.
  • aryl encompasses a ring system of up to 14 carbons atoms.
  • Aryl includes a carbocyclic aromatic ring fused with a 5- or 6-membered cycloalkyl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl and indanyl.
  • Aryloxy is RO-, where R is aryl.
  • Arylthio is RS-, where R is aryl.
  • Carbamoyl is the group NH 2 -C(O)- ; the nitrogen can be substituted with alkyl groups.
  • _V-(alkyl)carbamoyl is RNH-C(O)- and _V,-V-(alkyl) 2 carbamoyl is R 2 N-C(O)-, where the R groups are alkyl as defined herein and are the same or different.
  • R is a Ci-Cio alkyl group or a Ci-C 6 alkyl group.
  • Cycloalkyl is a hydrocarbyl group containing at least one saturated or partially unsaturated ring structure, and attached via a ring carbon. In various embodiments, it refers to a saturated or a partially unsaturated C 3 -Ci 2 cyclic moiety, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl.
  • Cycloalkyloxy is RO-, where R is cycloalkyl.
  • Cycloalkylalkyl refers to an alkyl moiety substituted with a cycloalkyl group, wherein cycloalkyl is as defined herein.
  • Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl and cyclohexylmethyl.
  • Cycloalkylidene refers to a divalent group formed from cycloalkane having two substituents on a single carbon of the cycloalkane. It can be represented in illustrative fashion by
  • cycloalkylidene is a divalent C 3 -C 12 cyclic moiety.
  • cycloalkylidene groups include cyclopropylidene, cyclobutylidene, cyclopentylidene and cyclohexylidene.
  • Dialkylamino refers to an RR'N- group where R and R' are independently alkyl as defined herein.
  • dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, methylethylamino and methylpropylamino.
  • R and R' are independently a C 1 -C 1O alkyl group or a Ci-C 6 alkyl group.
  • Dialkylaminoalkyl refers to an alkyl moiety substituted with a dialkylamino group, wherein dialkylamino is as defined herein.
  • dialkylaminoalkyl groups include, but are not limited to, dimethylaminomethyl and diethylaminomethyl.
  • “Feasible” refers to a structure or process that is capable of being accomplished; one that is possible, suitable, or logical.
  • a structure or process is “chemically feasible”, that structure or process is synthetically attainable, chemically stable to the typical ambient conditions and/or contributes to favorable biological properties such as efficacy, bioavailability and minimal toxicity for the intended use.
  • Chemically feasible structures are bound by the rules of electron bonding, whereby bonds can only be formed between atoms that are capable of forming bonds with one another. Likewise, chemically feasible processes can only produce structures that are themselves chemically feasible.
  • Halo refers to chloro (-Cl), bromo (-Br), fluoro (-F) or iodo (-1).
  • Haloalkoxy refers to an alkoxy group substituted with one or more halo groups. Examples of haloalkoxy groups include, but are not limited to, -OCF 3 , -OCHF 2 and -OCH 2 F. [0035] "Haloalkoxyalkyl” refers to an alkyl moiety substituted with a haloalkoxy group, wherein haloalkoxy is as defined herein. Examples of haloalkoxyalkyl groups include trifluoromethoxymethyl, trifluoroethoxymethyl and trifluoromethoxyethyl.
  • Haloalkyl refers to an alkyl moiety substituted with one or more halo groups.
  • haloalkyl groups include -CF 3 and -CHF 2 .
  • Heterocyclyl includes heteroaryl and heterocycloalkyl defined below and refers to an unsaturated, saturated, or partially unsaturated heterocyclic group. In various embodiments, it is a monocyclic, bicyclic or tricyclic group of 2 to 14 ring-carbon atoms. In addition to ring- carbon atoms, at least one ring has one or more heteroatoms selected from P, N, O and S. In various embodiments, the heterocyclic group is attached to another moiety through carbon or through a heteroatom, and is optionally substituted on carbon or a heteroatom.
  • heterocyclyl examples include azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,
  • Heterocyclylalkyl is an alkyl group substituted with a heterocyclyl.
  • Heterocyclyloxy is RO-, where R is heterocyclyl.
  • Heterocyclylthio is RS-, where R is heterocyclyl.
  • Heteroaryl is a heterocyclyl where at least one ring is aromatic. In various embodiments, it refers to a monocyclic, bicyclic or tricyclic ring having up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms in the ring selected from the group consisting of N, O and S.
  • heteroaryl examples include pyridyl, thienyl, furanyl, pyrimidyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazoyl, pyrrolyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, benzothienyl, indolyl, benzothiazolyl, Attorney Docket No. 8493-000092/WO/POA
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen containing heteroaryl.
  • Heteroaryloxy is RO-, where R is heteroaryl.
  • Heterocycloalkyl is a heterocyclyl where no rings are aromatic.
  • Heterocycloalkylidene refers to a divalent group formed from a heterocyclyl with two substituents on a single ring carbon. It can be represented in illustrative fashion by the
  • q determines the size of the ring and is one or greater.
  • Each Q is independently -CH 2 - or a heteroatom selected from -NH-, -O- and -S-, and when Q is methylene(-CH 2 -) or imino (-NH-), Q is optionally substituted with a group R 3 as defined herein.
  • “Hydroxyalkoxy” refers to an alkoxy group substituted with a hydroxyl group (-OH), wherein alkoxy is as defined herein. An example of hydroxyalkoxy is hydroxyethoxy.
  • Hydroxyalkyl refers to a linear or branched monovalent Ci-Cio hydrocarbon group substituted with at least one hydroxyl group.
  • hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.
  • substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less.
  • Sulphamoyl is NH 2 -S(O) 2 -; 'W-(alkyl)sulphamoyl” is RNH-S(O) 2 -; and "N,N- (alkyl) 2 sulphamoyl” is R 2 N-S(O) 2 -, where the R groups are alkyl as defined herein and are the same or different. In various embodiments, R is a C 1 -C 1O alkyl group or a Ci-C 6 alkyl group.
  • “Pharmaceutically-acceptable” means suitable for use in pharmaceutical preparations, generally considered as safe for such use, officially approved by a regulatory agency of a Attorney Docket No. 8493-000092/WO/POA
  • “Pharmaceutically-acceptable carrier” refers to a diluent, adjuvant, excipient, carrier, other ingredient, or combination of ingredients that is pharmaceutically-acceptable and with which a compound of the invention is administered.
  • “Pharmaceutically-acceptable salt” refers to a salt that may enhance desired pharmacological activity.
  • examples of pharmaceutically-acceptable salts include acid addition salts formed with inorganic or organic acids, metal salts and amine salts.
  • Examples of acid addition salts formed with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.
  • Examples of acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy- benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethane-sulfonic acid, benzenesulfonic acid, p- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid (p-TsOH), camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-en
  • “Therapeutically-effective amount” refers to an amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect treatment for the disease. “Therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, the weight, etc. of the subject to be treated.
  • Embraced herein, where applicable, are permissible isomers such as tautomers, racemates, enantiomers, diastereomers, atropisomers, configurational isomers of double bonds (E- and/or Z-), cis- and trans- configurations in ring substitution patterns, and isotopic variants.
  • is permissible isomers such as tautomers, racemates, enantiomers, diastereomers, atropisomers, configurational isomers of double bonds (E- and/or Z-), cis- and trans- configurations in ring substitution patterns, and isotopic variants.
  • the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is adjacent to the attachment of the Ar-C(O)-NH- group to the aryl or heteroaryl.
  • R 1 is hydroxyl and the compounds are characterized as hydroxamates. In another embodiment, R 1 is substituted aryl or heteroaryl and the compounds are characterized as arylamides.
  • Ar is phenyl. In various embodiments, the Cy 1 and -C(O)NH-R 1 groups are disposed on the phenyl in a 1,4-configuration, where Cy 1 is considered as the 1 -position.
  • Ar is thiophene.
  • the Cy 1 and - C(O)NH-R 1 groups are disposed on the thiophene in a 2,5-configuration, where Cy 1 is considered as the 2-position (with the S atom of the thiophene ring taken as the 1 -position).
  • Ar is pyridine.
  • the Cy 1 and -C(O)NH-R 1 groups are disposed on the pyridine in a 2,5-configuration, where Cy 1 is considered as the 2-position, or in a 3,6-configuration, where Cy 1 is considered as the 3-position (in all cases, the N atom of the pyridine ring is taken as the 1-position).
  • Ar is thiazole.
  • the Cy 1 and -C(O)NH-R 1 groups are disposed on the thiazole in a 2,4- or 2,5- configuration, where the Cy 1 is considered as the 2-position (with the S atom of the thiazole ring taken as the 1-position).
  • Cy 1 is C 3 - 7 cycloalkylidene, where the Ar and Cy 2 groups are substituted in a 1,1 -configuration on the C 3 - 7 ring.
  • the ring of cycloalkylidene is optionally substituted with one or more groups R as further defined herein.
  • the ring is completely saturated with H so that the variable n in Formula (I) is zero.
  • Cy 1 is cyclopropylidene, cyclobutylidene, or cyclopentylidene.
  • Cy 1 is a heterocyclic group with 1,1-disubstitution by the Ar and Cy 2 rings.
  • Examples include 5- to 7-membered rings containing at least one heteroatom selected from N, O, and S.
  • Carbon atoms in the 1,1-disubstituted heterocyclic ring are
  • tetrahydropyran-4,4-diyl i.e., O
  • Ar and Cy are attached to the 4-position of tetrahydropyran, with the oxygen position taken as position 1.
  • the ring Cy is a nitrogen containing heterocyclyl.
  • Cy is a 5-membered or 6-membered heterocyclyl. Examples include pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, dihydropyridine, pyrimidine, pyrazine, pyridazine, and triazines.
  • Cy 2 is a fused bicyclic ring system containing a 5- or 6-membered nitrogen containing heteroaryl ring fused to another ring.
  • Cy 2 is selected from
  • Cy is a heterocyclic group substituted by one or more oxo groups.
  • Non-limiting examples of such Cy 2 include:
  • At least one of the substituents on ring Cy is a cyclic group.
  • the cyclic group R 4 is a 5- or 6-membered ring nitrogen containing heteroaryl, optionally fused.
  • the cyclic group optionally contains one or more substituents R 5 , as further defined herein.
  • A, B and D are independently selected from the group consisting of halo, alkyl, nitro, cyano, hydroxyl, oxo, cycloalkyl, trifluoromethoxy, trifluoromethyl, trifluoroethyl, amino, carboxyl, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-/V- ethylamino, acetylamino, ,/V-methylcarbamoyl, ,/V-ethylcarbamoyl, JV,./V-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-/V-ethylcarbamoyl, JV,.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, B and D the carbon ranges for the groups alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, and the like include all ranges encompassed in the recited ranges C 1-1O and C 2 - I o-
  • C 1-1O and C 2-1O include a disclosure of Ci_ 6 and C 1-3 .
  • C 1-1 Q carbon-chain containing groups such as C 1-1 Q alkyl, C 2-1 Q alkenyl, C 2-1 Q Attorney Docket No. 8493-000092/WO/POA
  • alkynyl and so forth include the respective C 1-6 and C 1-3 shorter carbon-chains such as C 1-6 alkyl, C 1-3 alkyl, C 2 -6 alkenyl, C 2 -3 alkenyl, C 2 -6 alkynyl and C 2 -3 alkynyl.
  • each R 4 is independently H, halo, hydroxyl, oxo, nitro, cyano, trifluoromethyl, trifluoromethoxy, amino, carboxyl, carbamoyl, sulphamoyl, C 1-3 alkyl, C 2 - 3 alkenyl, C 2 - 3 alkynyl, C 1-3 alkoxy, C 1-3 alkanoyl, N-(C 1-3 alkyl)amino, N, N- (C 1-3 alkyl) 2 amino, C 1-3 alkanoylamino, N-(C 1-3 alkyl)carbamoyl, N, N- (C 1-3 alkyl) 2 carbamoyl, C 1-3 alkyl-S(O) a wherein a is 0, 1 or 2, NH 2 -S(O) 2 NH-, N-(Ci -3 alkyl) sulphamoyl, C 1-3 alkyl, C 2 - 3 alkenyl, C 2
  • Ar is phenyl, 5-member heteroaryl, or 6-member heteroaryl, wherein the heteroaryl contains one or more heteroatoms selected from ⁇ , S and O; and Attorney Docket No. 8493-000092/WO/POA
  • A, B and D are independently selected from halo, nitro, cyano, hydroxyl, oxo, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, Ci_ 6 alkoxy, Ci_ 6 alkanoyl, Ci_ 6 alkanoyloxy, N-(C 1-6 alkyl)amino, N,N-(C 1-6 alkyl) 2 amino, Ci_ 6 alkanoylamino, N-(C 1-6 alkyl)carbamoyl, N,N- (C 1-6 alkyl) 2 carbamoyl, Ci_ 6 alkyl-S(O) a wherein a is 0, 1 or 2, C 1-6 alkoxycarbonyl, N- (C 1-6 alkyl)sulphamo
  • a compound of Formula (I) contains a divalent Cy 1 linking a substituted or unsubstituted Cy 2 to -Ar-CONH-R 1 .
  • Each Ar, Cy 1 and Cy 2 can be optionally substituted with various substituents as defined as R 2 , R 3 and R 4 , respectively.
  • Formula (I) indicates that the attachment of substituents on Cy 1 , Cy 2 and Ar rings is variable.
  • compounds are selected from those of Formulae (I-a), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (1-1), (I-m), (I-n), (I-o), (I-p), (I-q), and (I-r) with substituents defined as in Formula (I):
  • a compound of the invention is used in inhibiting HDAC enzymes such as, for example, mammalian HDACs. More specifically, a compound of the invention can be used to treat or inhibit HDAC-mediated diseases or abnormalities.
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, and R 1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl.
  • R 1 is hydroxyl,
  • m is 0, 1 or 2 and each R 2 is independently fluoro, chloro, bromo, or methyl.
  • n is 0, 1 or 2 and each R 3 is, if present, a non-hydrogen substituent selected independently from methyl, ethyl, bromo, and trifruoromethyl, or two R 3 together form a spiro-ring on Cy 1 selected from
  • Each R 4 is independently selected from H, chloro, hydroxyl, methyl, ethyl, propyl, acetyl, propanoyl, butanoyl, methoxy, ethoxy, methoxymethyl, ethoxyethyl, propoxyethyl, methoxyethoxy, trifluoromethyl, hydroxyethoxy, dimethylamino, diethylamino, dimethylaminomethyl, diethylaminomethyl, dimethylaminoethoxy, trifluoromethoxymethyl, trifluoroethoxymethyl, benzyl, phenylethyl, trifluoromethylphenylethyl, phenoxymethyl, Attorney Docket No. 8493-000092/WO/POA
  • p is 2 or greater and two R 4 groups are substituted at adjacent positions of Cy 2 and form a 5- or 6-membered cyclic moiety to make a fused ring with Cy 2 , wherein the cyclic moiety can be carbocyclic or contain one or more heteroatoms selected from N, O and S; and the cyclic moiety is optionally substituted by one or more R 5 where such an optional substitution is chemically feasible.
  • fused rings include, but are not limited to:
  • s 0, 1, 2 or 3.
  • R 4 is not aryl, cycloalkyl or heterocyclyl, each R 4 is optionally substituted by one or more B where such an optional substitution is chemically feasible, and if R 4 is aryl, cycloalkyl or heterocyclyl, R 4 is optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible.
  • R 5 is independently selected from chloro, hydroxyl, oxo, methyl, ethyl, propyl, methoxy, ethoxy, methoxymethyl, ethoxyethyl, propoxyethyl, methoxyethoxy, trifruoromethyl, hydroxyethoxy, dimethylamino, diethylamino, dimethylaminomethyl, diethylaminomethyl, dimethylaminoethoxy, trifruoromethoxymethyl, trifluoroethoxymethyl, benzyl, phenylethyl, trifluoromethylphenylethyl, phenoxymethyl, fluorophenoxymethyl, phenylethylaminomethyl, benzylaminomethyl, triazinylmethyl, piperidinylmethyl, piperidinyloxy, trifluoromethylpiperidinylmethyl, pyridinyloxymethyl, pyridinylmethoxy, tetrahydr
  • the Cy 1 linker and the -CONHR 1 moiety are disposed about the phenyl ring of Formulae (I- a), (I-c) and (I-e) through (I-r) in either a 1,3- (meta) or a 1,4- (para) configuration.
  • R can be attached to any ring position of the phenyl ring which is not occupied by the Cy 1 linker and -CONHR 1 moiety and such attachment includes 1,2- (ortho), 1,3- (meta) and 1,4- (para) configurations wherein the Cy 1 linker is at position 1.
  • ortho-, meta- and para-configurations of R 2 mean attachment to positions 2, 3 and 4 of the phenyl ring as shown in Formulas (I-a) and (I-c), respectively.
  • R 2 is an ortho- substitution (i.e., position 2)
  • meta-CONHR 1 moiety is intended to be at position 5.
  • the invention provides a compound of Formula (I-a) and a pharmaceutically acceptable salt thereof: Attorney Docket No. 8493-000092/WO/POA wherein Cy 1 , R 1 , R 2 , R 3 and R 4 are as defined above for various aspects of Formula (I).
  • Cy 1 is cyclopropylidene;
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R 1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl;
  • m is 0 or 1 and R 2 is halo, C 1
  • R 6 and R 7 are independently selected from the functional groups of R 4 defined herein.
  • Table 1 provides non-limiting examples of compounds of Formula (I-aO) where m is zero where R 6 and R 7 together can form a cyclic moiety to make a fused ring with the thiazole ring (Cy 2 ), that fused ring is shown in the R 6 and R 7 columns of the table.
  • Table 1 Examples of Formula (I-aO)
  • R and R form a cyclic moiety.
  • the groups R and R are illustrated with the thiazolyl group (Cy ) to show their attachments to the thiazolyl ring.
  • Cy 1 is cyclopropylidene and the thiazole ring Cy 2 is substituted with a fused aryl, cycloalkyl, or heterocyclyl ring.
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R 1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl
  • Non-limiting examples of compounds of Formula (I-al) include the following compounds shown in Table 2 and pharmaceutically acceptable salts thereof:
  • the groups R 1 , R 4 , R 6 ', R 7 ', R 8 R 9 and R 10 can be selected to have the same combination of substituents given in the table fo Compounds al-01 to al-200 where such combinations are chemically feasible.
  • Cy 1 is cyclopropylidene and Cy 2 is substituted by R 4 being a monocyclic aryl, cycloalkyl or heterocyclyl.
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R 1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophen
  • R 4 is a ring
  • R 4 is optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • R 5 is as defined above.
  • Compounds of this embodiment include, but are not limited to, the following formulae where the groups R > 6 f ', r R> 7'', R , R , and R 10 are independently selected from H and the functional groups of R defined herein:
  • Non-limiting examples of Formulae (I-a7), (I-a8), (I-a9), (I-all), and (I-al2) include the following compounds and pharmaceutically acceptable salts thereof:
  • Table 3 provides non-limiting examples of compounds of Formula (I-al0) where m is zero and R 4 , R 6 ', R 7 ', and R 10 are H, as shown in Structure (AlO).
  • Cy 1 is cyclobutylidene, cyclopentylidene, cyclohexylidene or cycloheptylidene;
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH at a ring position adjacent to attachment of the - CONH-moiety, wherein R 1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, hetero
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R 1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; R is halo, alkyl or haloalkyl; m is 0 or 1 and R 2 is halo, alkyl or haloalkyl
  • Non-limiting examples of such compounds include compounds of Formulae (I-a'l) to (I-a'6) and pharmaceutically acceptable salts thereof:
  • the groups R 6 ', R 7 ', R 8 , R 9 , and R 10 are independently selected from H and the functional groups of R 5 defined herein, and wherein q is 2, 3, 4 or 5.
  • the groups R 1 , R 2 , R 4 , R 6 ', R 7 ', R 8 , R 9 and R 10 are selected to have the same combination of substituents given in the table for Compounds al-01 to al-200.
  • Non-limiting examples of such compounds include the following compounds and pharmaceutically acceptable salts thereof:
  • Cy 1 is cyclobutylidene, cyclopentylidene, cyclohexylidene or cycloheptylidene and Cy 2 is substituted with a monocyclic ring.
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R 1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; R 2 is halo, alkyl or haloalkyl; m is 0 or 1 and R 2 is halo, alkyl or haloalky
  • Non-limiting examples of such compounds include compounds of Formulae (I-a'7) to (I-a'12) and pharmaceutically acceptable salts thereof: Attorney Docket No. 8493-000092/WO/POA
  • the groups R 6 ', R 7 ', R 8 , R 9 , and R 10 are independently selected from H and the functional groups of R 5 defined herein and q is 2, 3, 4, or 5.
  • the groups R 1 , R 4 , R 6 ', R 7 ', R 8 , R 9 and R 10 are selected to have the same combination of substituents as those of Formulae (I-a7), (I-a8), (I-a9), (I-alO), (I-all), and (I-al2).
  • Non-limiting examples of such compounds include the following compounds and pharmaceutically acceptable salts thereof:
  • Cy 1 is heterocycloalkylidene;
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R 1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or Attorney Docket No. 8493-000092/WO/POA
  • alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl;
  • R 2 is halo, alkyl or haloalkyl;
  • m is 0 or 1 and R 2 is halo, alkyl or haloalkyl;
  • n is 0, 1 or 2 and each R 3 is independently methyl, ethyl, bromo, trifluoromethyl;
  • p is 0, 1 or 2 and each R 4 is independently selected from the group consisting of halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C 1-1 O alkyl, C 2-1 O alkenyl, C 2-1 O al
  • Cy 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 6 and R 7 are independently selected from groups R 4 ; q is 2, 3, 4 or 5 and each Q is independently -CH 2 - or a heteroatom selected from -NH-, -O- and -S-, and when Q is methylene (-CH 2 -) or imino (-NH-), Q is optionally substituted with a group R 3 .
  • Q adjacent the 1-position is not a heteroatom.
  • q is 2, 3, 4 or 5; each Q is independently -CH 2 - or a heteroatom selected from -NH-, -O- and -S-.
  • q is 2, 3, 4 or 5; each Q is independently -CH 2 - or a heteroatom selected from -NH-, -O- and -S-.
  • Cy 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Table 4 provides non-limiting examples of compounds of Formula (I-a"0) where m is zero, q is four, and Q is oxygen at the 4-position, as shown in Structure (A"0): Attorney Docket No. 8493-000092/WO/POA
  • R 6 and R 7 form a cyclic moiety.
  • the groups R 6 and R 7 are illustrated with the thiazolyl group (Cy 2 ) to show their attachments to the thiazolyl ring.
  • Cy 1 is heterocycloalkylidene;
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R 1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl;
  • R 2 is halo, alkyl or haloalkyl
  • R 6 ', R 7 ', R 8 , R 9 , and R 10 are independently selected from H and the functional groups of R 5 defined herein.
  • q is 2, 3, 4 or 5 and each Q is independently -CH 2 - or a heteroatom selected from -NH-, -O- and -S-, and when Q is methylene (-CH 2 -) or imino (-NH-), Q is optionally substituted with a group R .
  • Q adjacent the 1-position is not a heteroatom.
  • q is 2, 3, 4 or 5; each Q is independently -CH 2 - or a heteroatom selected from -NH-, -O- and -S-; and the groups R 1 , R 4 , R 6 ', R 7 ', R 8 , R 9 and R 10 can be selected to have the same combination of substituents given in the table for Compounds al-01 to al-200.
  • Cy 1 is independently selected to have the same combination of substituents given in the table for Compounds al-01 to al-200.
  • Cy 1 is heterocycloalkylidene; and one and only one R 4 is a monocyclic group.
  • R 1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH 2 or -OH at a ring position adjacent to attachment of the - CONH-moiety, wherein R 1 is optionally further substituted with one or more groups selected Attorney Docket No. 8493-000092/WO/POA
  • each Q is independently -CH 2 - or a heteroatom selected from -NH-, -O- and -S-; wherein R 1 , R 2 , and R 4 are as defined for various embodiments above, and wherein R 6 ', R 7 ', R 8 , R 9 , and R 10 are selected from H and the functional groups of R 5 defined herein.
  • the groups R 1 , R 4 , R 6 ', R 7 ', R 8 , R 9 and R 10 are selected to have the same Attorney Docket No. 8493-000092/WO/POA
  • Cy 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Table 5 provides non-limiting examples of compounds of Formula (I-a"10) where m is zero and R 4 , R 6 ', R 7 ', and R 10 are H, as shown in Structure (A" 10):
  • the invention provides a compound of Formula (I-b) and a pharmaceutically acceptable salt thereof: Attorney Docket No. 8493-000092/WO/POA Formula (l-b) wherein Cy 1 , R 1 , R 2 , R 3 and R 4 are as defined above for various aspects of Formula (I).
  • Cy 1 is cyclopropylidene; and R 4 is independently selected from the group consisting of H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C MO alkyl, C2-10 alkenyl,
  • R 6 and R 7 are selected from groups R 4 .
  • m is 0 and -CONH-R 1 is attached to the thiophene ring position adjacent the S atom.
  • the groups R 1 , R 6 and R 7 are selected to have the same combination of substituents given in the table for Compounds aO-01 to aO-126.
  • Cy 1 is cyclopropylidene; and R 4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring and R 4 is optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • Compounds of this embodiment include, but are not limited to, the following formulae: Attorney Docket No.
  • Formula (l-b2) (l-b3) Formula (l-b5) Formula (l-b6) where the groups R 6 ', R 7 ', R 8 , R 9 , and R 10 are independently selected from H and the functional groups of R 5 defined herein.
  • m is 0 and -CONH-R 1 is attached to the thiophene at a ring position adjacent to the S atom.
  • the groups R 1 , R 4 , R 6 ', R 7 ', R 8 , R 9 and R 10 are selected to have the same combination of substituents given in the table for Compounds al-01 to al-200.
  • Cy 1 is cyclopropylidene; and one and only one R 4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • R 4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • Compounds of this embodiment include, but are not limited to, those of the following formulae:
  • the groups R 6 ', R 7 ', R 8 , R 9 , and R 10 are independently selected from H and the functional groups of R 5 defined herein.
  • m is 0 and -CONH-R 1 is attached to the thiophene ring position adjacent the S atom.
  • the groups R 1 , R 4 , R 6 ', R 7 ', R 8 , R 9 and R 10 are selected to have the same combination of substituents as those of Compounds a7-01 through al2-04. That is, Compounds b7-01 through bl2-04 are like a7-01 through al2-04, except the former have thiophene where the latter have phenyl.
  • the invention provides a compound of Formula (I-c) and a pharmaceutically acceptable salt thereof:
  • Cy 1 is cyclopropylidene; and R 4 is independently selected from the group consisting of H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C 1-1 O alkyl, C 2-1 O alkenyl, C 2 - I o alkynyl, C 1-1 O alkoxy, C 1-1 O alkanoyl, C 1-1 O alkanoyloxy, N-(C 1-1 O alkyl)amino, alkyl) 2 amino, C 1-1 Q alkanoylamino, N-(C 1-1 Q alkyl)carbamoyl, NjN-(C 1-1 Q alkyl) 2 carbamoyl, C 1-1 Q Attorney Docket No. 8493-000092/WO/PO
  • alkyl-S(O) a wherein a is 0, 1 or 2, C 1-10 alkoxycarbonyl, NH 2 -S(O) 2 NH-, -V-(C 1-10 alkyl)sulphamoyl and alkyl) 2 sulphamoyl, wherein each R 4 is optionally substituted by one or more B where such an optional substitution is chemically feasible.
  • Non-limiting examples of such compounds include the following compounds and pharmaceutically acceptable salts thereof:
  • R 1 and R 2 are as defined above; and R 11 , R 12 and R 13 are independently selected from R 4 defined herein.
  • Cy 1 is cyclopropylidene; and one and only one R 4 is aryl, cycloalkyl or heterocycloalkyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • R 4 is aryl, cycloalkyl or heterocycloalkyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • Compounds of this embodiment include, but are not limited to, the following formulae:
  • Cy 1 is cyclopropylidene; and R 4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • Compounds of this embodiment include, but are not limited to, the following formulae:
  • groups R 6 ', R 7 ', R 8 , R 9 , and R 10 are independently selected from H and the functional groups of R 5 defined herein.
  • groups R 4 are H.
  • -C(O)NHR 1 is attached to the phenyl ring at a position p ⁇ r ⁇ to cyclopropylidene.
  • the groups R 1 , R 2 , R 6 ', R 7 ', R 8 , R 9 and R 10 are selected to have the same combination of substituents as those of Compounds a7-01 through al2-04. That is, Compounds c7-01 through cl2-04 are like a7-01 through al2-04, except the former have pyrimidine where the latter have thiazole.
  • the invention provides a compound of Formula (I-d) and a pharmaceutically acceptable salt thereof:
  • Cy 1 is cyclopropylidene; and R 4 is independently selected from the group consisting of H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C 1-1 O alkyl, C 2-1 O alkenyl, C 2-1 O alkynyl, C 1-1 O alkoxy, C 1-1 O alkanoyl, C 1-1 O alkanoyloxy, N-(C 1-1 O alkyl)amino, N,N-(Ci_io alkyl)2amino, C 1-1 O alkanoylamino, N-(C 1-1 O alkyl)carbamoyl, N,N-(Ci_io alkyl)2carbamoyl, C 1-1 O alkyl-S
  • R 1 and R 2 are as defined above; and R 11 , R 12 and R 13 are independently selected from the functional groups of R 4 defined herein.
  • Cy 1 is cyclopropylidene; and one and only one R 4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring and R 4 is optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • R 4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring and R 4 is optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • Compounds of this embodiment include, but are not limited to, the following formulae:
  • the groups R 6 ', R 7 ', R 8 , R 9 , and R 10 are independently selected from H and the functional groups of R 5 defined herein.
  • m is 0; both groups R 4 are H; and/or - CONH-R 1 is attached to the thiophene ring position adjacent the S atom.
  • the groups R 1 , R 6 ', R 7 ', R 8 , R 9 and R 10 are selected to have the same combination of substituents given in the table for each of Compounds al-01 to al-200.
  • Cy 1 is cyclopropylidene; and one and only one R 4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • R 4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring optionally further substituted by one or more R 5 where such an optional substitution is chemically feasible; and R 5 is as defined above.
  • Compounds of this embodiment include, but are not limited to, the following formulae: Attorney Docket No. 8493-000092/WO/POA
  • the groups R 6 ', R 7 ', R 8 , R 9 , and R 10 are independently selected from H and the functional groups of R 5 defined herein.
  • m is 0; both groups R 4 are H; and/or - CONH-R 1 is attached to the thiophene ring position adjacent the S atom.
  • the groups R 1 , R 6 ', R 7 ', R 8 , R 9 and R 10 are selected to have the same combination of substituents as those of Compounds a7-01 through al2-04. That is, Compounds d7-01 through dl2-04 are like a7-01 through al2-04, except the former have pyrimidine and thiophene where the latter have thiazole and phenyl, respectively.
  • the invention provides a compound selected from the group consisting of Formulae (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (M), (I-m), (I-n), (I-o), (I-p), (I-q), and (I-r), and a pharmaceutically acceptable salt thereof:
  • Non-limiting examples of such compounds include the following compounds and pharmaceutically acceptable salts thereof:
  • the invention provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof:
  • Cy 1 is cyclopropylidene, cyclopentylidene or tetrahydropyran-4,4-diylidene;
  • R 1 is hydroxyl or phenyl substituted with -NH 2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R 1 is optionally further substituted with one or more groups selected from amino, halo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
  • R 6 is Ci_ 3 alkyl, C 2 - 3 alkenyl, C 2 - 3 alkynyl, C 1-3 alkoxy, C 1-3 alkanoyl, imidazopyridinyl or pyridinyl, wherein if R 6 is not imidazopyridinyl or pyridinyl, R 6 is optionally substituted by one or more B where such an optional substitution is chemically feasible, and if R 6 is imidazopyridinyl or pyridinyl, R 6 is optionally further substituted by one or more R 5 ;
  • R 7 is Ci_ 3 alkyl, C 2 - 3 alkenyl, C 2 - 3 alkynyl, C 1-3 alkoxy or C 1-3 alkanoyl;
  • R 5 is independently selected from the group consisting of halo, nitro, cyano, hydroxyl, oxo, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, alkyl, C2-6 alkenyl, C2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, Ci_6 alkanoyloxy, N-(C 1-6 alkyl)amino, NN-(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N-(C 1-6 alkyl)carbamoyl, NN-(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkyl-S(O) a wherein a is 0, 1 or 2, C 1-6 alkoxycarbonyl, NH 2 -S(O) 2 NH-, N-(C 1-6 al
  • aryl, aryloxy, arylthio, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyl(C O)-, heterocyclyloxy and heterocyclylthio; wherein R 5 is optionally substituted by one or more D where such an optional substitution is chemically feasible;
  • B and D are independently selected from halo, nitro, cyano, hydroxyl, oxo, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 alkoxy, Ci_6 alkanoyl, Ci_6 alkanoyloxy, N-(C ⁇ - ⁇ alkyl)amino, N,N-(C ⁇ - ⁇ alkyl)2amino, Ci_6 alkanoylamino, N-(C ⁇ - ⁇ alkyl)carbamoyl, N,N- (C1-6 alkyl)2carbamoyl, Ci_6 alkyl-S(O) a wherein a is 0, 1 or 2, Ci_6 alkoxycarbonyl, N- (C 1-6 alkyl)sulphamoy
  • a compound of the present invention such as those of Formulae (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (1-1), (I-m), (I-n), (I-o), (I-p), (I-q), and (I-r) can be prepared according to the schemes described below, but it shall be appreciated that modifications of the illustrated process or other processes can also be used.
  • Cycloalkylidene linked HDAC inhibitors can be synthesized according to Scheme 1, showing preparation of inhibitors 8a and 8b where Ar is phenyl and where Cy 2 is a substituted thiazole.
  • ⁇ -cyano-p-methylbenzoic acid ester 1 is reacted with dibromide 2 (q is an integer from 1 to 6) to form cyano intermediate 3a, which is in turn reacted with hydrogen sulfide to yield thioamide compound 4a.
  • Thiazole intermediate 6 is prepared by reacting thioamide 4a with ⁇ -bromo carbonyl compound 5.
  • Substituents R 6 and R 7 on intermediate 5 are selected from H and the functional groups of R 4 defined herein and become the substituents on ring Cy 2 of the inhibitors.
  • Thiazole intermediate 6 is then reacted with 1,2-diamino aryl compound 7a to provide arylamide HDAC inhibitor 8a or with NH 2 OH to provide hydroxamate inhibitor 8b.
  • Scheme 1 can be genericized with respect to the group Ar of the HDAC inhibitors.
  • inhibitors 8' are synthesized from starting esters 1' by way of thioamide intermediate 4'.
  • Inhibitors with heterocycloalkylidene linkers Cy 1 can be synthesized analogously to Schemes 1 and 2 by reaction of starting compounds 1 or 1' with a dibromoether 2' as in Scheme 3.
  • Scheme 3 illustrates the synthesis when Ar in the inhibitor is a 1,4-substituted phenyl, with Cy 1 taken as position 1.
  • intermediate 5 is prepared containing a ring substituent at R' according to Scheme 4.
  • a first synthetic route begins with the reaction of an aminopyridine b with a chlorodiketone a to make an acyl imidazopyridine c, which is brominated to bromoketone
  • Cyanocycloalkylidene 3a is converted to urea compound 4a and reacted with aminoketone 5 to give ester 6.
  • Ester 6 is converted to arylamide 8a or to hydroxamate 8b.
  • pyrimidine compounds can be synthesized according to Scheme 7, where intermediate 6 is alkylated to form cycloalkylidene 3 before reaction to the hydroxamate or arylamide.
  • intermediate 6 of Scheme 7 can be alkylated as in Scheme 3 to form a heterocycloalkylidene analog of intermediate 3 (not shown).
  • the compounds of the present invention inhibit histone deacetylase and are useful to treat or ameliorate diseases mediated directly or indirectly by HDAC. Therefore, another aspect Attorney Docket No. 8493-000092/WO/POA
  • composition of the present invention is to provide a pharmaceutical composition comprising an effective amount of one or more compounds as described above.
  • a pharmaceutical composition comprising, in addition to one or more compounds described herein, at least one pharmaceutically-acceptable diluent, adjuvant, excipient, or carrier.
  • the composition can take any suitable form for the desired route of administration.
  • any suitable orally deliverable dosage form can be used, including without limitation tablets, capsules (solid- or liquid-filled), powders, granules, syrups and other liquids, elixirs, inhalants, troches, lozenges, and solutions.
  • Injectable compositions or iv infusions are also provided in the form of solutions, suspensions, and emulsions.
  • a pharmaceutical composition according to the present invention may contain one or more additional therapeutic agents, for example, to increase the efficacy or decrease the side effects.
  • a pharmaceutical composition further contains one or more additional therapeutic agents selected from active ingredients useful to treat or inhibit diseases mediated directly or indirectly by HDAC.
  • active ingredients are, without limitation, agents to treat or inhibit cancer, Huntington's disease, cystic fibrosis, liver fibrosis, renal fibrosis, pulmonary fibrosis, skin fibrosis, Rheumatoid arthritis, diabetes, stroke, amyotrophic lateral sclerosis, cardiac hypertrophy, heart failure or Alzheimer's disease.
  • an additional therapeutic agent to be included is an anti-cancer agent.
  • an anti-cancer agent include, but are not limited to, alkylating agents such as cyclophosphamide, dacarbazine, and cisplatin; antimetabolites such as methotrexate, mercaptopurine, thioguanine, fluorouracil, and cytarabine; plant alkaloids such as vinblastine, and paclitaxel; antitumor antibiotics such as doxorubicin, bleomycin, and mitomycin; hormones/antihormones such as prednisone, tamoxifen, and flutamide; other types of anticancer agents such as asparaginase, rituximab, trastuzumab, imatinib, retinoic acid and derivatives, colony- stimulating factors, amifostine, camptothecin, topotecan, thalidomide analogs such as len
  • Yet another aspect of the present invention is to provide a method of inhibiting or treating diseases arising from abnormal cell proliferation and/or differentiation in animal, comprising administering to said animal a therapeutically effective amount of one or more compounds according to the present invention.
  • the method of inhibiting or treating disease comprises administering to an animal a composition comprising an effective amount of one or more compounds of the invention and a pharmaceutically-acceptable carrier.
  • the composition to be administered may further contain a therapeutic agent such as anti-cancer agent.
  • a method of the present invention is particularly suitable for use with humans, but may be used with other animals, particularly mammals, such as, for example, non-human primates, companion animals, farm animals, laboratory animals, and wild and zoo animals.
  • a method of the present invention is particularly useful to treat diseases mediated directly or indirectly by HDAC since the compounds of the present invention have inhibitory activity against those molecules. In some embodiments, therefore, a method of the present invention is used in inhibiting or treating HDAC-mediated diseases.
  • Such disease examples include, but are not limited to, cell proliferative diseases such as cancer, autosomal dominant disorders such as Huntington's disease, genetic related metabolic disorder such as cystic fibrosis, fibrosis such as liver fibrosis, renal fibrosis, pulmonary fibrosis and skin fibrosis, autoimmune diseases such as Rheumatoid arthritis, diabetes, acute and chronic neurological diseases such as stroke, hypertrophy such as cardiac hypertrophy, heart failure including congestive heart failure, amyotrophic lateral sclerosis, and Alzheimer's disease.
  • cell proliferative diseases such as cancer
  • autosomal dominant disorders such as Huntington's disease
  • genetic related metabolic disorder such as cystic fibrosis
  • fibrosis such as liver fibrosis
  • renal fibrosis fibrosis
  • pulmonary fibrosis and skin fibrosis
  • autoimmune diseases such as Rheumatoid arthritis
  • diabetes acute and chronic neurological diseases
  • hypertrophy such as cardiac hypertrophy
  • heart failure
  • a method according to the present invention is applied to a patient with cancer, cystic fibrosis, or pulmonary fibrosis.
  • a method using a compound according to the present invention is used to treat or inhibit a cancer selected from bladder cancer, breast cancer, colon and rectal cancer, endometrial cancer, kidney (renal cell) cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, skin cancer (non-melanoma), and thyroid cancer.
  • Int-4 (0.1 Ig, 0.42 mmol) and Int-3 (O.lOg, 0.42 mmol) were dissolved in EtOH (10 mL) and heated to reflux under stirring for 20 minutes. The reaction mixture was evaporated under vacuum. The crude Int-5 (0.15g) was used in the next step without further purification. Int-5 (0.15g, 0.38 mmol) was dissolved in MeOH (6 mL) and treated with an aqueous solution of IN NaOH (2 mL). The reaction mixture was stirred for 2 hours and then IN aqueous HCl was Attorney Docket No. 8493-000092/WO/POA
  • Int-2 (0.2g, 16.51 mmol) was dissolved in a mixture of HBr/AcOH 33% (2 mL) and AcOH (4 mL). 93.3 ⁇ L Br 2 (1.1 equivalents (eq)) in chloroform (3 mL) was added slowly to the solution at room temperature. After 5 minutes the crystals in suspension were filtered out and worked out with water and EtOAc. The organic phase was dried with MgSO 4 and evaporated under vacuum. The crude product was used without further purification for next step. The procedure to synthesize Int-5 of Example 1 was followed to synthesize Int-4 but using Int-3. The same procedure to get Int-6 and Int-7 of Example 1 was used to synthesize Compound 6 from Int-4.
  • Example 7 N-(2-Amino-phenyl)-4- ⁇ l-[4-(2-methyl-imidazo[l,2- ⁇ ]pyridin-3-yl)- thiazol-2-yl] -cyclopentyl ⁇ -benzamide Attorney Docket No. 8493-000092/WO/POA
  • Example 1 The same procedure to get Int-2 and Int-3 of Example 1 was used to synthesize Int-3. Then the procedure to get Int-5 of Example 1 was followed for the synthesis of Int-4 and Int-7 but using 2-bromo-l-pyridin-3-yl-ethanone and 2-bromo-l-(2-methyl-imidazo[l,2- ⁇ ]pyridin-3- yl)-ethanone. Following the procedure to get Int-6 of Example 1, Int-5 and Int-8 were synthesized.
  • Example 8 N-(2-Amino-phenyl)-4-[4-(4-pyridin-3-yl-thiazol-2-yl)-tetrahydro-pyran- 4-yl]-benzamide
  • Preparation of Int-3 The procedure to get Int-2 of Example 1 was followed to synthesize Int-2 and Int-3 but using l-bromo-2-(2-bromo-ethoxy)-ethane.
  • Preparation of Compounds 6 and 9 The procedure to get Int-5 of Example 1 was followed for the synthesis of Int-4 and Int-7 but using 2-bromo-l-pyridin-3-yl-ethanone and 2- bromo-l-(2-methyl-imidazo[l,2- ⁇ ]pyridin-3-yl)-ethanone. The same procedure to get Int-6 and Compound 7 of Example 1 was used to synthesize Compound 6 and Compound 9 from Int-4 and Int-7, respectively.
  • Example 12 Ethyl-2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
  • Example 13 N-(2-amino-phenyl)-4-[l-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2- yl)-cyclopropyl] -benzamide
  • Example 14 te/t-butyl 2-(l-(4-(2-aminophenylcarbamoyl)phenyl) cyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
  • Example 13 (Compound aO-48)
  • Example 14 (Compound aO-57)
  • N-(2-aminophenyl)-4-(l-(4-methylthiazol-2-yl)cyclopropyl)benzamide Attorney Docket No. 8493-000092/WO/POA
  • l-Pyridin-3-yl-ethanone (2g, 16.52 mmol) was dissolved in a mixture of AcOH (8 rnL) and HBr (4 rnL). After stirring for 20 minutes, Br 2 (l.Oeq) in CHCl 3 (3 mL) was added in a period of 5 minutes. When the reaction was completed, the solids were filtered out and washed with water and extracted with EtOAc. The organic phase was dried, evaporated, and used for next step.
  • Example 53 (Compound a"12-02) Attorney Docket No. 8493-000092/WO/POA
  • Example 63 (Compound a"0-37) [0274] Similar procedure from Example 9 was followed to obtain the title compound using
  • Example 65 (Compound a"0-44) Attorney Docket No. 8493-000092/WO/POA
  • Example 70 (Compound aO-49) Attorney Docket No. 8493-000092/WO/POA
  • Example 72 (Compound e-08) Attorney Docket No. 8493-000092/WO/POA
  • Example 73 (Compound aO-51) [0297] Similar procedure from Example 29 was followed to obtain the title compound using
  • Example 75 (Compound a"0-42) [0301] A mixture of 2-cyclopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
  • HATU (1.28 g, 2.1 eq) and DIPEA (0.8 mL, 3.0 eq) were added and stirred at 50 0 C for 1 hour.
  • the reaction mixture was cooled down to room temperature and benzyl alcohol (172 mg, 1.0 eq) was added.
  • the reaction mixture was stirred at room temperature overnight.
  • Saturated aqueous solution of NaHCO 3 was added to the mixture and was then extracted with EtOAc. The organic phase was dried, evaporated and used for next step without further purification.
  • N-(2-amino-phenyl)-4-[4-(l-methyl-4-pyrazin-2-yl-lH-imidazol-2-yl)-tetrahydro- pyran-4-yl]-benzamide Attorney Docket No. 8493-000092/WO/POA
  • HDAC inhibitory activity of the compound of Example 1 was measured by two types of assays in which HDAC 1 and 6 were used as a target molecule. The first assay was carried out without preincubation after addition of the enzyme. The test compound was suspended in and titrated in DMSO. It was then spotted into a 384-well test plate. The enzyme, HDAC 1 or 6, was diluted in assay buffer containing 25mM Tris-HCl (pH 8.0), 137mM NaCl, 2.7mM KCl, and
  • the reaction was incubated at room temperature for about 15 minutes and relative fluorescence was read on an instrument reader.
  • the second assay is similar to the first assay described above, except that preincubation is carried out for about 3 hours after the enzyme is introduced.
  • the test compound was suspended in, and titrated in DMSO. It was then spotted into a 384-well test plate.
  • the enzyme, HDAC 1 or 6 was diluted in the same assay buffer as used in the previous assay and added to the pre-spotted compound.
  • the enzyme/compound mix was incubated at room temperature for about 3 hours.
  • the peptide substrate containing a fluorophore/quencher pair was diluted in the assay buffer and added to the compound/enzyme mix initiating the reaction.
  • the reaction incubated at room temperature for 45 minutes.
  • a concentrated developer solution was diluted in the assay buffer, and added to the reaction.
  • the reaction was incubated at room temperature for about 15 minutes and relative fluorescence was read on an instrument reader.
  • Table 6 shows IC 50 data for the compound tested with the protocols described above. Table 6. IC 50 of HDAC inhibitor compounds

Abstract

The present invention provides a compound of general Formula (I) having histone deacetylase (HDAC) inhibitory activity, a pharmaceutical composition comprising the compound, and a method useful to treat diseases using the compound.

Description

CYCLOALKYLIDENE AND HETEROCYCLOALKYLIDENE HISTONE DEACETYLASE INHIBITOR
COMPOUNDS
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. provisional application serial number 61/084,081 filed July 28, 2008. The disclosure of the application is hereby incorporated by reference.
FIELD
[0002] The present invention generally relates to a compound having enzyme inhibitory activity, pharmaceutical compositions comprising the compound, and methods useful for treating diseases.
BACKGROUND
[0003] Histones are protein components making up chromatin in association with DNA.
Histones are subject to covalent modifications of various enzymes such as, for example, histone deacetylase (HDAC), histone methyltransferase (HMT) and histone acetyl transferase (HAT). Covalent modifications of core histones influence protein-protein interaction and protein access to DNA.
[0004] HDACs catalyze deacetylation of lysine residues on histones and other proteins. It is known that low levels of histone-acetylation are associated with repression of gene expression. Therefore, abnormal HDAC activities could destroy the delicate balance in cell regulation. The HDACs belong to four structurally and functionally different phylogenetic classes: class I (HDAC-I, -2, -3, and -8) compounds are closely related to yeast RPD3; class Ha (HDAC-4, -5, - 7, and -9) and class lib (HDAC-6 and -10) share domains with yeast HDAC-I; class IV, recently described (comprising HDAC-Il), exhibits properties of both class I and class II HDACs. All the above HDACs are zinc dependent proteases. Class III HDACs have been identified on the basis of sequence similarity with Sir2, a yeast transcription repressor, and require the cofactor NAD+ for their deacetylase function. See, for example, Marielle Paris et al., Histone Deacetylase Inhibitors: From Bench to Clinic, JOURNAL OF MEDICINAL CHEMISTRY 51(11): 3330 - 3330 (2008).
[0005] It has been reported that HDAC activities play an important role in a variety of human disease states. Accordingly, an HDAC inhibitor can provide therapeutic benefits to a broad range of patients. Due to the therapeutic significance, various types of HDAC inhibitors Attorney Docket No. 8493-000092/WO/POA
have been developed to date. See, for example, Moradei et al., Histone Deacetylase Inhibitors: Latest Developments, Trends, and Prospects, CURR. MED. CHEM.: ANTI-CANCER AGENTS 5(5):529-560 (2005).
[0006] WO 2005/092899 mentions a series of compounds useful for inhibiting HDAC enzymatic activity where the compounds are amino or hydroxyl substituted aniline derivatives attached to various cyclic groups.
[0007] There is a continued need to develop new inhibitors to provide appropriate therapy for a variety of disease conditions implicated in HDAC activity.
SUMMARY [0008] In various embodiments, a compound having HDAC inhibitory activity, a composition comprising the compound, and a method useful to treat diseases arising from abnormal cell proliferation or differentiation are provided. [0009] The compound is of Formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000003_0001
Formula (I) wherein
Cy1 is cycloalkylidene or heterocycloalkylidene; Cy2 is cycloalkyl, aryl or heterocyclyl; Ar is aryl or heteroaryl; m is an integer from 0 to the maximum number of substitutable positions on Ar; n is an integer from 0 to the maximum number of substitutable positions on Cy1; p is an integer equal to the number of substitutable positions on Cy , wherein a substitutable position is one that, based on the valence of the ring atom occupying the position, can contain H or other substituent. Carbon ring atoms are substitutable, while O and S ring atoms are not substitutable. N ring atoms are substitutable or not, depending on valence. Further, the ring position of Cy2 occupied by Cy1 is not substitutble; Attorney Docket No. 8493-000092/WO/POA
R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH and aryl or heteroaryl is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; each R2 is independently selected from the group consisting of hydroxyl, oxo, halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, amino, carboxyl, carbamoyl, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, N-(C1-1O alkyl)amino, N,N- (C1-1O alkyl)2 amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, N,N-(Ci_io alkyl)2 carbamoyl, C1-10 alkyl-S(O)a wherein a is 0, 1 or 2, NH2-S(O)2NH-, N-(C1-10 alkyl)sulphamoyl, N,N-(Ci_io alkyl)2sulphamoyl, cycloalkyl, heterocyclyl and aryl; each R3 is independently selected from the group consisting of hydroxyl, oxo, halo, nitro, cyano, trifluoromethyl, trifluoromethoxy, amino, carboxyl, carbamoyl, sulphamoyl, C1-1O alkyl, C2_io alkenyl, C2_io alkynyl, C1-1O alkoxy, C1-1O alkanoyl, N-(C1-1O alkyl)amino, N,N-
(C1-1O alkyl)2 amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, N,N-(Ci_io alkyl)2 carbamoyl, C1-10 alkyl-S(O)a wherein a is 0, 1 or 2, NH2-S(O)2NH-, N-(C1-10 alkyl)sulphamoyl, N,N-(C1-10 alkyl)2sulphamoyl, cycloalkyl, heterocyclyl and aryl, wherein each R is optionally substituted by one or more A where such an optional substitution is chemically feasible; and alternatively or in addition two groups R3 are substituted on the same carbon ring atom of Cy1 and together with the carbon ring atom of Cy1 form a ring situated on Cy1 in a spiro configuration; in various embodiments the spiro-ring on Cy1 is cycloalkyl or heterocycloalkyl, containing from 3 to 7 ring atoms, and is optionally substituted by one or more A; each R4 is independently selected from the group consisting of H, halo, nitro, cyano, hydroxyl, oxo, hydroxy(Ci_io alkyl), amino(Ci_io alkyl), haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2_io alkenyl, C2_io alkynyl, C1-1O alkoxy, hydroxy (C1-10 alkoxy)(Ci_i0 alkoxy), (C1-10 alkoxy)(Ci_i0 alkoxy), (C1-10 alkoxy)(Ci_io alkyl), C1-10 alkanoyl, C1-10 alkanoyloxy, N-(C1-10 alkyl)amino, N,N-(C1-10 alkyl)2amino, C1-10 alkanoylamino, N-(C1-10 alkyl)carbamoyl, N,N-(C1-10 alkyl)2carbamoyl,
C1-10 alkyl-S(O)a wherein a is 0, 1 or 2, C1-10 alkoxycarbonyl, NH2-S(O)2NH-, NH2-CO- Attorney Docket No. 8493-000092/WO/POA
NH-, N-(Ci-io alkyl)sulphamoyl, N,N-(Ci_io alkyl)2sulphamoyl, aryl, arylalkyl, aryloxy, arylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyl(C=O)-, heterocyclyloxy and heterocyclylthio, wherein if R4 is not aryl, cycloalkyl or heterocyclyl, each R4 is optionally substituted by one or more B where such an optional substitution is chemically feasible, and if R4 is aryl, cycloalkyl or heterocyclyl,
R4 is optionally further substituted by one or more R5 where such an optional substitution is chemically feasible, or when p is 2 or greater, two R4 groups together can form a 5- or 6-membered cyclic moiety to make a fused ring with Cy2 ring, wherein the cyclic moiety can contain one or more heteroatoms selected from Ν, O and S and the fused ring is optionally substituted by one or more R5 where such an optional substitution is chemically feasible; each R5 is independently selected from halo, nitro, cyano, hydroxyl, oxo, hydroxy(Ci_io alkyl), amino(Ci-io alkyl), haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, Ci_i0 alkyl, C2-io alkenyl, C2-io alkynyl, Ci_io alkoxy, hydroxy(Ci_i0 alkoxy)(Ci_io alkoxy), (C1-10 alkoxy)(Ci_i0 alkoxy), (C1-10 alkoxy)(Ci_i0 alkyl), C1-10 alkanoyl, C1-10 alkanoyloxy, N-(C1-10 alkyl)amino, N,N-(C1-10 alkyl)2amino, C1-10 alkanoylamino, N-(C1-10 alkyl)carbamoyl, N,N-(C1-10 alkyl)2carbamoyl, C1-10 alkyl-S(O)a wherein a is 0, 1 or 2, C1-10 alkoxycarbonyl, NH2-S(O)2NH-, NH2-CO-NH-, N-(C1-10 alkyl)sulphamoyl, N,N-(C1-10 alkyl)2sulphamoyl, aryl, arylalkyl, aryloxy, arylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyl(C=O)-, heterocyclyloxy and heterocyclylthio, wherein each R5 is optionally substituted by one or more D where such an optional substitution is chemically feasible; and
A, B and D are independently selected from halo, nitro, cyano, hydroxyl, oxo, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 alkanoyl, C1-10 alkanoyloxy, N-(C1-10 alkyl)amino, N,N-(C1-10 alkyl)2amino, C1-10 alkanoylamino, N-(C1-10 alkyl)carbamoyl, N, N- (C1-10 alkyl)2carbamoyl, C1-10 alkyl-S(O)a wherein a is 0, 1 or 2, C1-10 alkoxycarbonyl, N- (Ci-io alkyl)sulphamoyl, JV,JV-(C1-10 alkyl)2sulphamoyl, H2NS(O)2NH-, N-(Ci-I0 alkyl)ΝHS(O)2ΝH-, JV,JV-(C1-10 alkyl)2NS(O)2NH-, aryl, aryloxy, arylthio, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyl(C=O)-, heterocyclyloxy and heterocyclylthio. Attorney Docket No. 8493-000092/WO/POA
[0010] Pharmaceutical compositions comprise an HDAC-inhibitory effective amount of one or more compounds described herein and a pharmaceutically-acceptable carrier.
[0011] Methods of inhibiting or treating diseases arising from abnormal cell proliferation and differentiation comprise administering to a subject a therapeutically effective amount of one or more compounds described herein. Other methods involve co-therapies by administering one or more of the compounds together with other anti-cancer agents.
[0012] The compounds above are more fully described in the detailed description that follows.
DETAILED DESCRIPTION [0013] The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or uses.
Definitions
[0014] "Alkenyl" refers to a straight or branched hydrocarbyl group with at least one site of unsaturation, i.e. a carbon-carbon, sp2 double bond. In an embodiment, alkenyl has from 2 to 12 carbon atoms. In some embodiments, alkenyl is a C2-CiO alkenyl group or a C2-C6 alkenyl group.
Examples of alkenyl group include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl
(-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).
[0015] "Alkanoyl" is the group RC(O)-; "alkanoyloxy" is RC(O)O-; and "alkanoylamino" is RC(O)NR'-; where R is an alkyl group as defined herein, and R' is H or alkyl. In various embodiments, R is a C1-C1O alkyl group or a Ci-C6 alkyl group.
[0016] "Alkoxy" is RO- where R is alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy and propoxy.
[0017] "Alkoxyalkyl" refers to an alkyl moiety substituted with an alkoxy group. Examples of alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl and ethoxyethyl. [0018] "Alkoxycarbonyl" is ROC(O)-, where R is an alkyl group as defined herein. In various embodiments, R is a C1-C1O alkyl group or a Ci-C6 alkyl group.
[0019] "Alkyl" refers to a straight or branched chain saturated hydrocarbyl group. In an embodiment, alkyl has from 1 to 12 carbon atoms. In some embodiments, alkyl is a C1-C1O alkyl group or a C1-C6 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Attorney Docket No. 8493-000092/WO/POA
[0020] "Alkylamino" refers to an amino group substituted with one or more alkyl groups.
'W-(alkyl)amino" is RNH- and 'W,N-(alkyl)2amino" is R2N-, where the R groups are alkyl as defined herein and are the same or different. In various embodiments, R is a C1-C1O alkyl group or a Ci-C6 alkyl group. Examples of alkylamino groups include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino, and methylethylamno.
[0021] "Alkylaminoalkyl" refers to an alkyl moiety substituted with an alkylamino group, wherein alkylamino is as defined herein. Examples of alkylaminoakyl groups include methylaminomethyl and ethylaminomethyl.
[0022] "Alkynyl" refers to a straight or branched carbon-chain group with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. In an embodiment, alkynyl has from 2 to 12 carbon atoms. In some embodiments, alkynyl is a C2-CiO alkynyl group or a C2-C6 alkynyl group. Examples of alkynyl groups include acetylenic (-C≡CH) and propargyl (-CH2C≡CH).
[0023] "Aryl" refers to a monocyclic, bicyclic or tricyclic carbon ring system of up to 7 atoms in each ring, wherein at least one ring is aromatic. In various embodiments, aryl encompasses a ring system of up to 14 carbons atoms. Aryl includes a carbocyclic aromatic ring fused with a 5- or 6-membered cycloalkyl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl and indanyl.
[0024] "Aryloxy" is RO-, where R is aryl. "Arylthio" is RS-, where R is aryl.
[0025] "Carbamoyl" is the group NH2-C(O)- ; the nitrogen can be substituted with alkyl groups. _V-(alkyl)carbamoyl is RNH-C(O)- and _V,-V-(alkyl)2 carbamoyl is R2N-C(O)-, where the R groups are alkyl as defined herein and are the same or different. In various embodiments, R is a Ci-Cio alkyl group or a Ci-C6 alkyl group.
[0026] "Cycloalkyl" is a hydrocarbyl group containing at least one saturated or partially unsaturated ring structure, and attached via a ring carbon. In various embodiments, it refers to a saturated or a partially unsaturated C3-Ci2 cyclic moiety, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl.
[0027] "Cycloalkyloxy" is RO-, where R is cycloalkyl.
[0028] "Cycloalkylalkyl" refers to an alkyl moiety substituted with a cycloalkyl group, wherein cycloalkyl is as defined herein. Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl and cyclohexylmethyl. Attorney Docket No. 8493-000092/WO/POA
[0029] "Cycloalkylidene" refers to a divalent group formed from cycloalkane having two substituents on a single carbon of the cycloalkane. It can be represented in illustrative fashion by
the following formula, W wherein q determines the size of the ring and is one or greater. For example, q=2 makes cyclobutylidene. In various embodiments, cycloalkylidene is a divalent C3-C12 cyclic moiety. Examples of cycloalkylidene groups include cyclopropylidene, cyclobutylidene, cyclopentylidene and cyclohexylidene.
[0030] "Dialkylamino" refers to an RR'N- group where R and R' are independently alkyl as defined herein. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, methylethylamino and methylpropylamino. In various embodiments, R and R' are independently a C1-C1O alkyl group or a Ci-C6 alkyl group.
[0031] "Dialkylaminoalkyl" refers to an alkyl moiety substituted with a dialkylamino group, wherein dialkylamino is as defined herein. Examples of dialkylaminoalkyl groups include, but are not limited to, dimethylaminomethyl and diethylaminomethyl.
[0032] "Feasible" refers to a structure or process that is capable of being accomplished; one that is possible, suitable, or logical. When a structure or process is "chemically feasible", that structure or process is synthetically attainable, chemically stable to the typical ambient conditions and/or contributes to favorable biological properties such as efficacy, bioavailability and minimal toxicity for the intended use. Chemically feasible structures are bound by the rules of electron bonding, whereby bonds can only be formed between atoms that are capable of forming bonds with one another. Likewise, chemically feasible processes can only produce structures that are themselves chemically feasible.
[0033] "Halo" refers to chloro (-Cl), bromo (-Br), fluoro (-F) or iodo (-1).
[0034] "Haloalkoxy" refers to an alkoxy group substituted with one or more halo groups. Examples of haloalkoxy groups include, but are not limited to, -OCF3, -OCHF2 and -OCH2F. [0035] "Haloalkoxyalkyl" refers to an alkyl moiety substituted with a haloalkoxy group, wherein haloalkoxy is as defined herein. Examples of haloalkoxyalkyl groups include trifluoromethoxymethyl, trifluoroethoxymethyl and trifluoromethoxyethyl.
[0036] "Haloalkyl" refers to an alkyl moiety substituted with one or more halo groups. Examples of haloalkyl groups include -CF3 and -CHF2. Attorney Docket No. 8493-000092/WO/POA
[0037] "Heterocyclyl" includes heteroaryl and heterocycloalkyl defined below and refers to an unsaturated, saturated, or partially unsaturated heterocyclic group. In various embodiments, it is a monocyclic, bicyclic or tricyclic group of 2 to 14 ring-carbon atoms. In addition to ring- carbon atoms, at least one ring has one or more heteroatoms selected from P, N, O and S. In various embodiments, the heterocyclic group is attached to another moiety through carbon or through a heteroatom, and is optionally substituted on carbon or a heteroatom. Examples of heterocyclyl include azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof.
[0038] "Heterocyclylalkyl" is an alkyl group substituted with a heterocyclyl. [0039] "Heterocyclyloxy" is RO-, where R is heterocyclyl. "Heterocyclylthio" is RS-, where R is heterocyclyl. [0040] "Heteroaryl" is a heterocyclyl where at least one ring is aromatic. In various embodiments, it refers to a monocyclic, bicyclic or tricyclic ring having up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms in the ring selected from the group consisting of N, O and S. Non-limiting examples of heteroaryl include pyridyl, thienyl, furanyl, pyrimidyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazoyl, pyrrolyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, benzothienyl, indolyl, benzothiazolyl, Attorney Docket No. 8493-000092/WO/POA
benzooxazolyl, benzimidazolyl, isoindolyl, benzotriazolyl, purinyl, thianaphthenyl and pyrazinyl. Attachment of heteroaryl can occur via an aromatic ring, or, if heteroaryl is bicyclic or tricyclic and one of the rings is not aromatic or contains no heteroatoms, through a non-aromatic ring or a ring containing no heteroatoms. "Heteroaryl" is also understood to include the N-oxide derivative of any nitrogen containing heteroaryl.
[0041] "Heteroaryloxy" is RO-, where R is heteroaryl.
[0042] "Heterocycloalkyl" is a heterocyclyl where no rings are aromatic.
[0043] "Heterocycloalkylidene" refers to a divalent group formed from a heterocyclyl with two substituents on a single ring carbon. It can be represented in illustrative fashion by the
formula
Figure imgf000010_0001
where q determines the size of the ring and is one or greater. Each Q is independently -CH2- or a heteroatom selected from -NH-, -O- and -S-, and when Q is methylene(-CH2-) or imino (-NH-), Q is optionally substituted with a group R3 as defined herein. [0044] "Hydroxyalkoxy" refers to an alkoxy group substituted with a hydroxyl group (-OH), wherein alkoxy is as defined herein. An example of hydroxyalkoxy is hydroxyethoxy. [0045] "Hydroxyalkyl" refers to a linear or branched monovalent Ci-Cio hydrocarbon group substituted with at least one hydroxyl group. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.
[0046] If a substituent is described as being "optionally substituted", the substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less.
[0047] "Sulphamoyl" is NH2-S(O)2-; 'W-(alkyl)sulphamoyl" is RNH-S(O)2-; and "N,N- (alkyl)2 sulphamoyl" is R2N-S(O)2-, where the R groups are alkyl as defined herein and are the same or different. In various embodiments, R is a C1-C1O alkyl group or a Ci-C6 alkyl group.
[0048] "Pharmaceutically-acceptable" means suitable for use in pharmaceutical preparations, generally considered as safe for such use, officially approved by a regulatory agency of a Attorney Docket No. 8493-000092/WO/POA
national or state government for such use, or being listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
[0049] "Pharmaceutically-acceptable carrier" refers to a diluent, adjuvant, excipient, carrier, other ingredient, or combination of ingredients that is pharmaceutically-acceptable and with which a compound of the invention is administered.
[0050] "Pharmaceutically-acceptable salt" refers to a salt that may enhance desired pharmacological activity. Examples of pharmaceutically-acceptable salts include acid addition salts formed with inorganic or organic acids, metal salts and amine salts. Examples of acid addition salts formed with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Examples of acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy- benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethane-sulfonic acid, benzenesulfonic acid, p- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid (p-TsOH), camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-enel-carboxylic acid, gluco-heptonic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic) acid, 3-phenylpropionic acid, trimethyl-acetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy-naphthoic acids, salicylic acid, stearic acid and muconic acid. Examples of metal salts include salts with sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions. Examples of amine salts include salts with ammonia and organic nitrogenous bases strong enough to form salts with carboxylic acids.
[0051] "Therapeutically-effective amount" refers to an amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect treatment for the disease. "Therapeutically effective amount" can vary depending on the compound, the disease and its severity, and the age, the weight, etc. of the subject to be treated.
[0052] Embraced herein, where applicable, are permissible isomers such as tautomers, racemates, enantiomers, diastereomers, atropisomers, configurational isomers of double bonds (E- and/or Z-), cis- and trans- configurations in ring substitution patterns, and isotopic variants. Attorney Docket No. 8493-000092/WO/POA
[0053] In one embodiment, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000012_0001
Formula (I) wherein m, n, p, Cy1, Cy2, Ar, R1, R2, R3 and R4 are as defined above. [0054] In various embodiments, the substitution with -NH2 or -OH on aryl or heteroaryl of
R1 is adjacent to the attachment of the Ar-C(O)-NH- group to the aryl or heteroaryl.
[0055] In an embodiment, R1 is hydroxyl and the compounds are characterized as hydroxamates. In another embodiment, R1 is substituted aryl or heteroaryl and the compounds are characterized as arylamides. [0056] In an embodiment, Ar is phenyl. In various embodiments, the Cy1 and -C(O)NH-R1 groups are disposed on the phenyl in a 1,4-configuration, where Cy1 is considered as the 1 -position.
[0057] In an embodiment, Ar is thiophene. In various embodiments, the Cy1 and - C(O)NH-R1 groups are disposed on the thiophene in a 2,5-configuration, where Cy1 is considered as the 2-position (with the S atom of the thiophene ring taken as the 1 -position).
[0058] In an embodiment, Ar is pyridine. In various embodiments, the Cy1 and -C(O)NH-R1 groups are disposed on the pyridine in a 2,5-configuration, where Cy1 is considered as the 2-position, or in a 3,6-configuration, where Cy1 is considered as the 3-position (in all cases, the N atom of the pyridine ring is taken as the 1-position). [0059] In an embodiment, Ar is thiazole. In various embodiments, the Cy1 and -C(O)NH-R1 groups are disposed on the thiazole in a 2,4- or 2,5- configuration, where the Cy1 is considered as the 2-position (with the S atom of the thiazole ring taken as the 1-position).
[0060] In an embodiment, Cy1 is C3-7 cycloalkylidene, where the Ar and Cy2 groups are substituted in a 1,1 -configuration on the C3-7 ring. The ring of cycloalkylidene is optionally substituted with one or more groups R as further defined herein. In various embodiments, the ring is completely saturated with H so that the variable n in Formula (I) is zero. In particular embodiments, Cy1 is cyclopropylidene, cyclobutylidene, or cyclopentylidene. Attorney Docket No. 8493-000092/WO/POA
[0061] In an embodiment, Cy1 is a heterocyclic group with 1,1-disubstitution by the Ar and Cy2 rings. Examples include 5- to 7-membered rings containing at least one heteroatom selected from N, O, and S. In preferred embodiments, there is no heteroatom substitution in Cy1 adjacent the 1,1- attachment of Ar and Cy2. Carbon atoms in the 1,1-disubstituted heterocyclic ring are
O optionally substituted with one or more oxo groups (i.e., 17MV^), and substitutable positions on the ring are optionally substituted with 1 or more groups R3. In various embodiments, the only substituent R3 is an oxo group on carbon. In other embodiments, all substitutable positions contain H, so that the variable n in Formula (I) is zero. A non-limiting example of Cy1 is
tetrahydropyran-4,4-diyl (i.e., O ), where Ar and Cy are attached to the 4-position of tetrahydropyran, with the oxygen position taken as position 1.
[0062] In an embodiment, the ring Cy is a nitrogen containing heterocyclyl. In various embodiments, Cy is a 5-membered or 6-membered heterocyclyl. Examples include pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, dihydropyridine, pyrimidine, pyrazine, pyridazine, and triazines. In various embodiments, Cy2 is a fused bicyclic ring system containing a 5- or 6-membered nitrogen containing heteroaryl ring fused to another ring.
[0063] In an embodiment, Cy2 is selected from
Figure imgf000013_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000014_0001
where the wavy lines show a position of attachment of the Cy1 group and each optional R4 group is attached to any other available positions on the Cy2 ring.
[0064] In some embodiments, Cy is a heterocyclic group substituted by one or more oxo groups. Non-limiting examples of such Cy2 include:
Figure imgf000014_0002
where the wavy lines show a position of attachment of the Cy1 group and each optional R4 group is attached to any other available positions on the Cy2 ring.
[0065] In various embodiments, at least one of the substituents on ring Cy is a cyclic group. In various embodiments, the cyclic group R4 is a 5- or 6-membered ring nitrogen containing heteroaryl, optionally fused. The cyclic group optionally contains one or more substituents R5, as further defined herein.
[0066] In an embodiment, A, B and D are independently selected from the group consisting of halo, alkyl, nitro, cyano, hydroxyl, oxo, cycloalkyl, trifluoromethoxy, trifluoromethyl, trifluoroethyl, amino, carboxyl, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-/V- ethylamino, acetylamino, ,/V-methylcarbamoyl, ,/V-ethylcarbamoyl, JV,./V-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-/V-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, ,/V-methylsulphamoyl, JV-ethylsulphamoyl, JV,./V-dimethylsulphamoyl, JV,./V-diethylsulphamoyl, N-methy\-N- ethylsulphamoyl, aryl, and heterocyclyl.
[0067] In the definitions herein of R1, R2, R3, R4, R5, A, B and D, the carbon ranges for the groups alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkanoyloxy, alkanoylamino, and the like include all ranges encompassed in the recited ranges C1-1O and C2-Io- For example, in non-limiting fashion C1-1O and C2-1O include a disclosure of Ci_6 and C1-3. In various embodiments, C1-1Q carbon-chain containing groups such as C1-1Q alkyl, C2-1Q alkenyl, C2-1Q Attorney Docket No. 8493-000092/WO/POA
alkynyl and so forth include the respective C1-6 and C1-3 shorter carbon-chains such as C1-6 alkyl, C1-3 alkyl, C2-6 alkenyl, C2-3 alkenyl, C2-6 alkynyl and C2-3 alkynyl.
[0068] In an embodiment when Ar is phenyl or 5- or 6-member heteroaryl, m is 0; in another embodiment, m is 1; in another embodiment, m is 2. [0069] In the Tables that follow, examples are given with m=0 or m=l. When m=0, the entry in the R2 column reads H (hydrogen) to indicate that all substituents are H. When m=l, the entry in the R column gives the identity and position of the single non-hydrogen substituent. [0070] In particular embodiments, the variables are further exemplified as follows: each R4 is independently H, halo, hydroxyl, oxo, nitro, cyano, trifluoromethyl, trifluoromethoxy, amino, carboxyl, carbamoyl, sulphamoyl, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, C1-3 alkanoyl, N-(C1-3 alkyl)amino, N, N- (C1-3 alkyl)2 amino, C1-3 alkanoylamino, N-(C1-3 alkyl)carbamoyl, N, N- (C1-3 alkyl)2 carbamoyl, C1-3 alkyl-S(O)a wherein a is 0, 1 or 2, NH2-S(O)2NH-, N-(Ci-3 alkyl) sulphamoyl, N1N-(Cu3 alkyl)2sulphamoyl, imidazolyl, triazolyl, pyridinyl, imidazopyridinyl, pyrazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, aryl, cycloalkyl or heterocyclyl, wherein if R4 is not aryl, cycloalkyl or heterocyclyl, each R4 is optionally substituted by one or more B where such an optional substitution is chemically feasible, and if R4 is aryl, cycloalkyl or heterocyclyl, R4 is optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; each R5 is independently selected from the group consisting of halo, nitro, cyano, hydroxyl, oxo, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, Ci_3 alkyl, C2_6 alkenyl, C2_6 alkynyl, C1-6 alkoxy, Ci_6 alkanoyl, C1-6 alkanoyloxy, N-(C1-6 alkyl)amino, N, N- (C1-6 alkyl)2amino, C1-6 alkanoylamino, N-(C1-6 alkyl)carbamoyl, N,N-(C1-6 alkyl)2carbamoyl, C1-6 alkyl-S(O)a wherein a is 0, 1 or 2, C1-6 alkoxycarbonyl, NH2-S(O)2NH-, N-(Ci-6 alkyl)sulphamoyl, MN-(C1-6 alkyl)2sulphamoyl, aryl, aryloxy, arylthio, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyl(C=O)-, heterocyclyloxy and heterocyclylthio, wherein R5 is optionally substituted by one or more D where such an optional substitution is chemically feasible;
Ar is phenyl, 5-member heteroaryl, or 6-member heteroaryl, wherein the heteroaryl contains one or more heteroatoms selected from Ν, S and O; and Attorney Docket No. 8493-000092/WO/POA
A, B and D are independently selected from halo, nitro, cyano, hydroxyl, oxo, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci_6 alkoxy, Ci_6 alkanoyl, Ci_6 alkanoyloxy, N-(C1-6 alkyl)amino, N,N-(C1-6 alkyl)2amino, Ci_6 alkanoylamino, N-(C1-6 alkyl)carbamoyl, N,N- (C1-6 alkyl)2carbamoyl, Ci_6 alkyl-S(O)a wherein a is 0, 1 or 2, C1-6 alkoxycarbonyl, N- (C1-6 alkyl)sulphamoyl, -YN-(C1-6 alkyl)2sulphamoyl, H2NS(O)2NH-, N-(Ci-6 alkyl)ΝHS(O)2ΝH-, N1N-(Ci* alkyl)2NS(O)2NH-, aryl, aryloxy, arylthio, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyl(C=O)-, heterocyclyloxy and heterocyclylthio. [0071] A compound of Formula (I) contains a divalent Cy1 linking a substituted or unsubstituted Cy2 to -Ar-CONH-R1. Each Ar, Cy1 and Cy2 can be optionally substituted with various substituents as defined as R2, R3 and R4, respectively. Formula (I) indicates that the attachment of substituents on Cy1, Cy2 and Ar rings is variable. [0072] In particular embodiments, compounds are selected from those of Formulae (I-a), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (1-1), (I-m), (I-n), (I-o), (I-p), (I-q), and (I-r) with substituents defined as in Formula (I):
Figure imgf000016_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000017_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000018_0001
ancj (R3)π Formula (l-r)
Figure imgf000018_0003
Figure imgf000018_0002
[0073] Compounds defined above are useful to inhibit HDACs. In one embodiment, therefore, a compound of the invention is used in inhibiting HDAC enzymes such as, for example, mammalian HDACs. More specifically, a compound of the invention can be used to treat or inhibit HDAC-mediated diseases or abnormalities.
[0074] In an embodiment of the compounds of Formulae (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (M), (I-m), (I-n), (I-o), (I-p), (I-q), and (I-r), one or more (including all) of the substituents R1, R2, R3, R4 and R5 are further limited as follows:
[0075] R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, and R1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl. In particular embodiments, R1 is hydroxyl,
Figure imgf000018_0004
2-hydroxyphenyl 2-aminophenyl 2-amino-6-fluorophenyl 2-amino-5-fluorophenyl 2-amino-5-trifluoromethylphenyl Attorney Docket No. 8493-000092/WO/POA
Figure imgf000019_0001
-aminobiphenyl-3-yl 4'-fluoro-4-aminobiphenyl-3-yl 2-amino-5
Figure imgf000019_0002
-(thiophen-2-yl)phenyl
Figure imgf000019_0003
'-chloro-2-amino-5-(thiophen-2-yl)phenyl 5'-methyl-2-amino-5-(thiophen-2-yl)phenyl 2-amino-5-(thiophen-3-yl)phenyl
Figure imgf000019_0004
-aminopyridin-3-yl 4-amino-l-phenyl-l//-pyrazol-3-yl 2-amino-5-(3-hydroxy-3-methylbut-l-ynyl)phenyl
-amino-5-
Figure imgf000019_0005
.4.4-trifluoro-3-hydroxy-3- 2-amino-5-(3-(l-hydroxycyclopropyl)
(trifluoromethyl)but-l -ynyl)phenyl 2-amino-5-(3-cyclopropylprop-l-ynyl)phenyl prop- 1 -ynyl)phenyl Attorney Docket No. 8493-000092/WO/POA
Figure imgf000020_0001
3-amino-6-phenylpyridin-2-yl 4'.6-difluoro-4-aminobiphenyl-3-yl 4-amino-4'-fluoro-6-cyanobiphenyl-3-yl
Figure imgf000020_0002
4-(2-(4-fluorophenyl)ethynyl)-2-aminophenyl 4-(2-(pyπdin-2-yl)ethynyl)-2-aminophenyl QJ- 4-(2-(tπmethylsilyl)ethynyl)-2-aminophenyl
[0076] m is 0, 1 or 2 and each R2 is independently fluoro, chloro, bromo, or methyl. [0077] n is 0, 1 or 2 and each R3 is, if present, a non-hydrogen substituent selected independently from methyl, ethyl, bromo, and trifruoromethyl, or two R3 together form a spiro-ring on Cy1 selected from
Figure imgf000020_0004
and
Figure imgf000020_0003
For example, compounds containing such a spiro moiety include
Figure imgf000020_0005
[0078] Each R4 is independently selected from H, chloro, hydroxyl, methyl, ethyl, propyl, acetyl, propanoyl, butanoyl, methoxy, ethoxy, methoxymethyl, ethoxyethyl, propoxyethyl, methoxyethoxy, trifluoromethyl, hydroxyethoxy, dimethylamino, diethylamino, dimethylaminomethyl, diethylaminomethyl, dimethylaminoethoxy, trifluoromethoxymethyl, trifluoroethoxymethyl, benzyl, phenylethyl, trifluoromethylphenylethyl, phenoxymethyl, Attorney Docket No. 8493-000092/WO/POA
fluorophenoxymethyl, phenylethylaminomethyl, benzylaminomethyl, triazinylmethyl, piperidinylmethyl, piperidinyloxy, trifluoromethylpiperidinylmethyl, pyridinyloxymethyl, pyridinylmethoxy, tetrahydropyrazinyloxy, methylpiperazinylmethyl, pyridyl, thienyl, furanyl, pyrimidyl, imidazolyl, pyridinyl, triazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazoyl, pyrrolyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, benzothienyl, indolyl, imidazopyridinyl, pyrazolopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoindolyl, benzotriazolyl, purinyl, thianaphthenyl, 1-methylcyclopropyl, trifluoroethyl, methoxypropyl, JV,./V-dimethylaminopropyl, 1-carboxycyclopropyl, N,N- dimethylcarbamoylcyclopropyl, pyridin-2-ylmethyl, 5-trifluoromethylpyridin-2-ylmethyl, N,N- dimethylcarbamoyl, morpholinylcarbonyl, t-butylcarbamoyl, morpholinoethoxycarbonyl, benzoyl, picolinoyl, quinoxa-6-linylcarbonyl, cyclopropylcarbonyl, propionyl, methoxypropanoyl, JV,./V-dimethylaminopropanoyl, 5-trifluoromethylpyridin-2-yl, 5- chloropyridin-2-yl, 5-cyclopropylpyridin-2-yl, 5-chloropyrimidin-2-yl, 2-methoxyphenyl, A- carboxyphenyl, JV,./V-dimethylcarbamoylphenyl, 2-chlorophenyl, 1-methylcyclopropoxycarbonyl, t-butoxycarbonyl, 2-trifluoromethylprop-2-oxycarbonyl, methylsulfonyl, trifluoroethylsulfonyl, 5-trifluoromethylpyridin-3-ylsulfonyl, pyridin-3-ylsulfonyl, phenylsulfonyl, cyclopropylsulfonyl, pyridin-2-yl, 5-trifluoromethylpyridin-2-yl, phenyl, and cyclopropyl; or
[0079] p is 2 or greater and two R4 groups are substituted at adjacent positions of Cy2 and form a 5- or 6-membered cyclic moiety to make a fused ring with Cy2, wherein the cyclic moiety can be carbocyclic or contain one or more heteroatoms selected from N, O and S; and the cyclic moiety is optionally substituted by one or more R5 where such an optional substitution is chemically feasible. Examples of such fused rings include, but are not limited to:
Figure imgf000021_0001
wherein s is 0, 1, 2 or 3.
[0080] If R4 is not aryl, cycloalkyl or heterocyclyl, each R4 is optionally substituted by one or more B where such an optional substitution is chemically feasible, and if R4 is aryl, cycloalkyl or heterocyclyl, R4 is optionally further substituted by one or more R5 where such an optional substitution is chemically feasible. Attorney Docket No. 8493-000092/WO/POA
[0081] R5 is independently selected from chloro, hydroxyl, oxo, methyl, ethyl, propyl, methoxy, ethoxy, methoxymethyl, ethoxyethyl, propoxyethyl, methoxyethoxy, trifruoromethyl, hydroxyethoxy, dimethylamino, diethylamino, dimethylaminomethyl, diethylaminomethyl, dimethylaminoethoxy, trifruoromethoxymethyl, trifluoroethoxymethyl, benzyl, phenylethyl, trifluoromethylphenylethyl, phenoxymethyl, fluorophenoxymethyl, phenylethylaminomethyl, benzylaminomethyl, triazinylmethyl, piperidinylmethyl, piperidinyloxy, trifluoromethylpiperidinylmethyl, pyridinyloxymethyl, pyridinylmethoxy, tetrahydropyrazinyloxy, methylpiperazinylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3- yl, pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl, pyrrolidin-3-ylmethyl, pyrrolidin-1-ylethoxy, pyrrolidin-2-ylethoxy, pyrrolidin-3-ylethoxy, imidazol-1-ylmethyl, imidazol-2-ylmethyl, imidazol-4-ylmethyl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, imidazolidin-1- ylmethyl, imidazolidin-2-ylmethyl, imidazolidin-4-ylmethyl, imidazolin-1-yl, imidazolin-2-yl, imidazolin-4-yl, pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolin-1-yl, pyrazolin-3- yl, pyrazolin-4-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-1- ylmethyl, piperidin-2-ylmethyl, piperidin-3-ylmethyl, piperidin-4-ylmethyl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, morpholin-2- ylmethyl, morpholin-3-ylmethyl, morpholin-4-ylmethyl, morpholin-2-ylethoxy, morpholin-3- ylethoxy and morpholin-4-ylethoxy.
[0082] In various embodiments, the Cy1 linker and the -CONHR1 moiety are disposed about the phenyl ring of Formulae (I- a), (I-c) and (I-e) through (I-r) in either a 1,3- (meta) or a 1,4- (para) configuration. R can be attached to any ring position of the phenyl ring which is not occupied by the Cy1 linker and -CONHR1 moiety and such attachment includes 1,2- (ortho), 1,3- (meta) and 1,4- (para) configurations wherein the Cy1 linker is at position 1. In the Tables that follow, ortho-, meta- and para-configurations of R2 mean attachment to positions 2, 3 and 4 of the phenyl ring as shown in Formulas (I-a) and (I-c), respectively. Where R2 is an ortho- substitution (i.e., position 2), meta-CONHR1 moiety is intended to be at position 5.
[0083] In one embodiment, the invention provides a compound of Formula (I-a) and a pharmaceutically acceptable salt thereof: Attorney Docket No. 8493-000092/WO/POA
Figure imgf000023_0001
wherein Cy1, R1, R2, R3 and R4 are as defined above for various aspects of Formula (I).
[0084] In an embodiment of Formula (I-a), Cy1 is cyclopropylidene; R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; m is 0 or 1 and R2 is halo, C1-1O alkyl or haloalkyl; n is 0, 1 or 2 and each R is independently methyl, ethyl, bromo, trifluoromethyl; p is 2 and each R4 is independently selected from the group consisting of H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino,
Figure imgf000023_0002
alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, N,N-(Ci_io alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-1O alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-1O alkyl) sulphamoyl and N,N-(Ci_io alkyl)2sulphamoyl, or p is 2 or greater and two R4 groups form a 5- or 6-membered cyclic moiety to make a fused ring with the thiazole ring (Cy2), wherein the cyclic moiety can contain one or more heteroatoms selected from Ν, O and S, wherein each R4 is optionally substituted by one or more B where such an optional substitution is chemically feasible.
[0085] Νon-limiting examples of such compounds include compounds of Formula (I-a0) and pharmaceutically acceptable salts thereof:
Figure imgf000023_0003
Formula (1-aO) Attorney Docket No. 8493-000092/WO/POA
wherein R6 and R7 are independently selected from the functional groups of R4 defined herein. Table 1 provides non-limiting examples of compounds of Formula (I-aO) where m is zero where R6 and R7 together can form a cyclic moiety to make a fused ring with the thiazole ring (Cy2), that fused ring is shown in the R6 and R7 columns of the table. Table 1. Examples of Formula (I-aO)
Figure imgf000024_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000025_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000026_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000027_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000028_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000029_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000030_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000031_0003
* wherein R and R form a cyclic moiety. The groups R and R are illustrated with the thiazolyl group (Cy ) to show their attachments to the thiazolyl ring.
[0086] In another embodiment of Formula (I-a), Cy1 is cyclopropylidene and the thiazole ring Cy2 is substituted with a fused aryl, cycloalkyl, or heterocyclyl ring. Also, R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; R is halo, alkyl or haloalkyl; m is 0 or 1 and R2 is halo, alkyl or haloalkyl; n is 0, 1 or 2 and each R3 is independently methyl, ethyl, bromo, trifluoromethyl; p is 1 or greater, wherein one and only one R i4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring; and the other R4, if present, are not aryl, cycloalkyl or heterocyclyl, optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. Compounds of this embodiment include, but are not limited to, compounds of the following formulae, where R6', R7', R8, R9, and R10 are independently selected from H and the functional groups of R5 defined herein:
Figure imgf000031_0002
Figure imgf000031_0001
(l-a2) Attorney Docket No. 8493-000092/WO/POA
Figure imgf000032_0001
Figure imgf000032_0002
(l-a6)
[0087] Non-limiting examples of compounds of Formula (I-al) include the following compounds shown in Table 2 and pharmaceutically acceptable salts thereof:
Figure imgf000032_0003
Figure imgf000032_0004
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000033_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000034_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000035_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000036_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000037_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000038_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000039_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000040_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000041_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000042_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000043_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000044_0001
[0088] In particular embodiments of Formulae (I-a2) to (I-a6), the groups R1, R4, R6', R7', R8 R9 and R10 can be selected to have the same combination of substituents given in the table fo Compounds al-01 to al-200 where such combinations are chemically feasible. Attorney Docket No. 8493-000092/WO/POA
[0089] In yet another embodiment of Formula (I-a), Cy1 is cyclopropylidene and Cy2 is substituted by R4 being a monocyclic aryl, cycloalkyl or heterocyclyl. Further, R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; R is halo, alkyl or haloalkyl; m is 0 or 1 and R2 is halo, alkyl or haloalkyl; n is 0, 1 or 2 and each R3 is independently methyl, ethyl, bromo, trifluoromethyl; p is 1 or greater; and one and only one R is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring while other R4, if present, are not aryl, cycloalkyl, or heterocyclyl. When R4 is a ring, R4 is optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. [0090] Compounds of this embodiment include, but are not limited to, the following formulae where the groups R > 6f', r R> 7'', R , R , and R 10 are independently selected from H and the functional groups of R defined herein:
Figure imgf000045_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000046_0001
(l-a11) ; ancl
Figure imgf000046_0002
(R2)m Formula (l-a12) _
[0091] Non-limiting examples of Formulae (I-a7), (I-a8), (I-a9), (I-all), and (I-al2) include the following compounds and pharmaceutically acceptable salts thereof:
Figure imgf000046_0003
Compound a8-02
Compound a8-01
Compound a8-03
Figure imgf000046_0004
Compound a9-02 Compound a9-03
Figure imgf000046_0005
Compound all-01
Figure imgf000046_0006
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000047_0001
Compound a 12-01 Compound al2-02
Figure imgf000047_0002
and
Compound al2-03
Figure imgf000047_0003
Compound al2-04
[0092] Table 3 provides non-limiting examples of compounds of Formula (I-al0) where m is zero and R4, R6', R7', and R10 are H, as shown in Structure (AlO).
Figure imgf000047_0004
Structure (A10)
Figure imgf000047_0005
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000048_0002
[0093] In an embodiment of Formula (I-a), Cy1 is cyclobutylidene, cyclopentylidene, cyclohexylidene or cycloheptylidene; R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the - CONH-moiety, wherein R1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; m is 0 or 1 and R2 is halo, alkyl or haloalkyl; n is 0, 1 or 2 and each R3 is independently methyl, ethyl, bromo, trifluoromethyl; p is 0, 1 or 2 and each R4 is independently selected from the group consisting of halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2- io alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, NN-(C1-1O alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, NN-(C1-1O alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-1O alkoxycarbonyl, NH2-S(O)2NH-, N-(Ci_io alkyl) sulphamoyl and NN-(C1-1O alkyl)2sulphamoyl, wherein each R4 is optionally substituted by one or more B where such an optional substitution is chemically feasible. In a particular embodiment, Cy1 is cyclopentylidene.
[0094] Νon-limiting examples of such compounds include compounds of Formula (I-a'0) and pharmaceutically acceptable salts thereof:
Figure imgf000048_0001
Formula (l-a'O) wherein q is 2, 3, 4 or 5; R1 and R2 are as defined above; and R6 and R7 are selected from groups R4. In specific embodiments, R1, R2, R6 and R7 can be selected to have the same combination of substituents given in the table for Compounds aO-01 to aO-126. [0095] In another embodiment of Formula (I-a), Cy1 is cyclobutylidene, cyclopentylidene, cyclohexylidene or cycloheptylidene and Cy2 is substituted with with a fused ring R4. Further, Attorney Docket No. 8493-000092/WO/POA
R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; R is halo, alkyl or haloalkyl; m is 0 or 1 and R2 is halo, alkyl or haloalkyl; n is 0, 1 or 2 and each R3 is independently methyl, ethyl, bromo, trifluoromethyl; p is 1 or greater; and one and only one R4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. In a particular embodiment, Cy1 is cyclopentylidene .
[0096] Non-limiting examples of such compounds include compounds of Formulae (I-a'l) to (I-a'6) and pharmaceutically acceptable salts thereof:
Figure imgf000049_0001
Formula (l-a'1 ), Formula (l-a'2),
Formula
Figure imgf000049_0002
Formula
Figure imgf000049_0003
Attorney Docket No. 8493-000092/WO/POA
where the groups R6', R7', R8, R9, and R10 are independently selected from H and the functional groups of R5 defined herein, and wherein q is 2, 3, 4 or 5. In particular embodiments, for each value of q, the groups R1, R2, R4, R6', R7', R8, R9 and R10 are selected to have the same combination of substituents given in the table for Compounds al-01 to al-200. Non-limiting examples of such compounds include the following compounds and pharmaceutically acceptable salts thereof:
Figure imgf000050_0001
Compound a'1-27 Compound a'1-29
[0097] In yet another embodiment of Formula (I-a), Cy1 is cyclobutylidene, cyclopentylidene, cyclohexylidene or cycloheptylidene and Cy2 is substituted with a monocyclic ring. Further, R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; R2 is halo, alkyl or haloalkyl; m is 0 or 1 and R2 is halo, alkyl or haloalkyl; n is 0, 1 or 2 and each R3 is independently methyl, ethyl, bromo, trifluoromethyl; p is 1 or greater and one and only one R4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring and R4 is optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. In a particular embodiment, Cy1 is cyclopentylidene .
[0098] Non-limiting examples of such compounds include compounds of Formulae (I-a'7) to (I-a'12) and pharmaceutically acceptable salts thereof: Attorney Docket No. 8493-000092/WO/POA
,
Figure imgf000051_0001
where the groups R6', R7', R8, R9, and R10 are independently selected from H and the functional groups of R5 defined herein and q is 2, 3, 4, or 5. In various embodiments, the groups R1, R4, R6', R7', R8, R9 and R10 are selected to have the same combination of substituents as those of Formulae (I-a7), (I-a8), (I-a9), (I-alO), (I-all), and (I-al2). Non-limiting examples of such compounds include the following compounds and pharmaceutically acceptable salts thereof:
Figure imgf000051_0002
Compound a'7-01 _ , !., « «„
Compound a'7-02 Compound a 10-02
[0099] In a further embodiment of Formula (I-a), Cy1 is heterocycloalkylidene; R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or Attorney Docket No. 8493-000092/WO/POA
alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; R2 is halo, alkyl or haloalkyl; m is 0 or 1 and R2 is halo, alkyl or haloalkyl; n is 0, 1 or 2 and each R3 is independently methyl, ethyl, bromo, trifluoromethyl; p is 0, 1 or 2 and each R4 is independently selected from the group consisting of halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, N,N-(Ci_io alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, N,N-(Ci_io alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-10 alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-10 alkyl) sulphamoyl and NjN-(C1-1O alkyl)2sulphamoyl, wherein each R4 is optionally substituted by one or more R5 where such an optional substitution is chemically feasible. In a particular
embodiment, Cy1 is
Figure imgf000052_0001
[00100] Νon-limiting examples of such compounds include compounds of Formula (I-a"0) and pharmaceutically acceptable salts thereof:
Figure imgf000052_0002
Formula (l-a"0) wherein R6 and R7 are independently selected from groups R4; q is 2, 3, 4 or 5 and each Q is independently -CH2- or a heteroatom selected from -NH-, -O- and -S-, and when Q is methylene (-CH2-) or imino (-NH-), Q is optionally substituted with a group R3. In various embodiments, Q adjacent the 1-position is not a heteroatom. In particular embodiments, q is 2, 3, 4 or 5; each Q is independently -CH2- or a heteroatom selected from -NH-, -O- and -S-. In a particular
embodiment, Cy1 is
Figure imgf000052_0003
[0100] Table 4 provides non-limiting examples of compounds of Formula (I-a"0) where m is zero, q is four, and Q is oxygen at the 4-position, as shown in Structure (A"0): Attorney Docket No. 8493-000092/WO/POA
Figure imgf000053_0001
Table 4. Examples of Structure (A"0).
Figure imgf000053_0002
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000054_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000055_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000056_0001
wherein R6 and R7 form a cyclic moiety. The groups R6 and R7 are illustrated with the thiazolyl group (Cy2) to show their attachments to the thiazolyl ring.
[0101] In another embodiment of Formula (I-a), Cy1 is heterocycloalkylidene; R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R1 is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; R2 is halo, alkyl or haloalkyl; m is 0 or 1 and R2 is halo, alkyl or haloalkyl; n is 0, 1 or 2 and each R3 is independently methyl, ethyl, bromo, trifluoromethyl; p is 1 or greater; and one and only one R4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring and R4 is optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. Compounds of this embodiment include, but are not limited to, the following formulae and pharmaceutically acceptable salts thereof: Attorney Docket No. 8493-000092/WO/POA
Figure imgf000057_0001
where the groups R6', R7', R8, R9, and R10 are independently selected from H and the functional groups of R5 defined herein. In non-limiting examples of such compounds, q is 2, 3, 4 or 5 and each Q is independently -CH2- or a heteroatom selected from -NH-, -O- and -S-, and when Q is methylene (-CH2-) or imino (-NH-), Q is optionally substituted with a group R . In various embodiments, Q adjacent the 1-position is not a heteroatom. In particular embodiments, q is 2, 3, 4 or 5; each Q is independently -CH2- or a heteroatom selected from -NH-, -O- and -S-; and the groups R1, R4, R6', R7', R8, R9 and R10 can be selected to have the same combination of substituents given in the table for Compounds al-01 to al-200. In a particular embodiment, Cy1
Figure imgf000057_0002
[0102] In yet another embodiment of Formula (I-a), Cy1 is heterocycloalkylidene; and one and only one R4 is a monocyclic group. Further, R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the - CONH-moiety, wherein R1 is optionally further substituted with one or more groups selected Attorney Docket No. 8493-000092/WO/POA
from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; R2 is halo, alkyl or haloalkyl; m is 0 or 1 and R2 is halo, alkyl or haloalkyl; n is 0, 1 or 2 and each R3 is independently methyl, ethyl, bromo, trifluoromethyl; p is 1 or greater; and one and only one R4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring and R4 is optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. Heterocycloalkylidene-containing compounds of this embodiment include, but are not limited to, those of the following formulae and pharmaceutically acceptable salts thereof:
Figure imgf000058_0001
wherein q is 2, 3, 4 or 5; each Q is independently -CH2- or a heteroatom selected from -NH-, -O- and -S-; wherein R1, R2, and R4 are as defined for various embodiments above, and wherein R6', R7', R8, R9, and R10 are selected from H and the functional groups of R5 defined herein. In various embodiments, the groups R1, R4, R6', R7', R8, R9 and R10 are selected to have the same Attorney Docket No. 8493-000092/WO/POA
combination of substituents as those of Formulae (I-a7), (I-a8), (I-a9), (I-all), and (I-al2). In a
particular embodiment, Cy1 is
Figure imgf000059_0001
[0103] Table 5 provides non-limiting examples of compounds of Formula (I-a"10) where m is zero and R4, R6', R7', and R10 are H, as shown in Structure (A" 10):
Figure imgf000059_0002
Structure (A"10).
Table 5. Example of Structure (A" 10).
Figure imgf000059_0003
[0104] In one embodiment, the invention provides a compound of Formula (I-b) and a pharmaceutically acceptable salt thereof: Attorney Docket No. 8493-000092/WO/POA
Figure imgf000060_0001
Formula (l-b) wherein Cy1, R1, R2, R3 and R4 are as defined above for various aspects of Formula (I).
[0105] In an embodiment of Formula (I-b), Cy1 is cyclopropylidene; and R4 is independently selected from the group consisting of H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, CMO alkyl, C2-10 alkenyl,
C2-10 alkynyl, CMO alkoxy, CMO alkanoyl, CMO alkanoyloxy, iV-(Ci-io alkyl)amino, NN-(Ci-io alkyl)2amino, CMO alkanoylamino, N-(Ci-W alkyl)carbamoyl, NN-(Ci_io alkyl)2carbamoyl, CMO alkyl-S(O)a wherein a is 0, 1 or 2, CM0 alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-10 alkyl) sulphamoyl and NN-(C1-1O alkyl)2sulphamoyl, wherein each R4 is optionally substituted by one or more B where such an optional substitution is chemically feasible. Νon-limiting examples of such compounds include compounds of Formula (I-b0) and pharmaceutically acceptable salts thereof:
Figure imgf000060_0002
wherein R6 and R7 are selected from groups R4. In various embodiments, m is 0 and -CONH-R1 is attached to the thiophene ring position adjacent the S atom. Illustratively, the groups R1, R6 and R7 are selected to have the same combination of substituents given in the table for Compounds aO-01 to aO-126.
[0106] In an embodiment of Formula (I-b), Cy1 is cyclopropylidene; and R4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring and R4 is optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. Compounds of this embodiment include, but are not limited to, the following formulae: Attorney Docket No. 8493-000092/WO/POA
Figure imgf000061_0001
Formula (l-b2)
Figure imgf000061_0002
(l-b3)
Figure imgf000061_0004
Formula (l-b5)
Figure imgf000061_0003
Formula (l-b6) where the groups R6', R7', R8, R9, and R10 are independently selected from H and the functional groups of R5 defined herein. In non-limiting embodiments, m is 0 and -CONH-R1 is attached to the thiophene at a ring position adjacent to the S atom. In various embodiments, the groups R1, R4, R6', R7', R8, R9 and R10 are selected to have the same combination of substituents given in the table for Compounds al-01 to al-200.
[0107] In an embodiment of Formula (I-b), Cy1 is cyclopropylidene; and one and only one R4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. Compounds of this embodiment include, but are not limited to, those of the following formulae:
R1 Formula (l-b8)
Figure imgf000061_0005
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000062_0001
where the groups R6', R7', R8, R9, and R10 are independently selected from H and the functional groups of R5 defined herein. In particular embodiments, m is 0 and -CONH-R1 is attached to the thiophene ring position adjacent the S atom. In various embodiments, the groups R1, R4, R6', R7', R8, R9 and R10 are selected to have the same combination of substituents as those of Compounds a7-01 through al2-04. That is, Compounds b7-01 through bl2-04 are like a7-01 through al2-04, except the former have thiophene where the latter have phenyl.
[0108] In one embodiment, the invention provides a compound of Formula (I-c) and a pharmaceutically acceptable salt thereof:
Figure imgf000062_0002
wherein Cy1, R1, R2, R3 and R4 are as defined above for various aspects of Formula (I).
[0109] In an embodiment of Formula (I-c), Cy1 is cyclopropylidene; and R4 is independently selected from the group consisting of H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-Io alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino,
Figure imgf000062_0003
alkyl)2amino, C1-1Q alkanoylamino, N-(C1-1Q alkyl)carbamoyl, NjN-(C1-1Q alkyl)2carbamoyl, C1-1Q Attorney Docket No. 8493-000092/WO/POA
alkyl-S(O)a wherein a is 0, 1 or 2, C1-10 alkoxycarbonyl, NH2-S(O)2NH-, -V-(C1-10 alkyl)sulphamoyl and
Figure imgf000063_0001
alkyl)2sulphamoyl, wherein each R4 is optionally substituted by one or more B where such an optional substitution is chemically feasible. Non-limiting examples of such compounds include the following compounds and pharmaceutically acceptable salts thereof:
Figure imgf000063_0002
wherein R1 and R2 are as defined above; and R11, R12 and R13 are independently selected from R4 defined herein.
[0110] In an embodiment of Formula (I-c), Cy1 is cyclopropylidene; and one and only one R4 is aryl, cycloalkyl or heterocycloalkyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. Compounds of this embodiment include, but are not limited to, the following formulae:
Figure imgf000063_0003
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000064_0002
(l-c5) and
Figure imgf000064_0001
Formula (l-c6) wherein p is 2; and R6', R7', R8, R9 and R10 are selected from H and groups R5. In specific embodiments, R1, R2, R6', R7', R8, R9 and R10 are selected to have the same combination of substituents given in the table for Compounds al-01 to a 1-200.
[0111] In an embodiment of Formula (I-c), Cy1 is cyclopropylidene; and R4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. Compounds of this embodiment include, but are not limited to, the following formulae:
and
Figure imgf000064_0003
where the groups R6', R7', R8, R9, and R10 are independently selected from H and the functional groups of R5 defined herein. In various embodiments, groups R4 are H. In various embodiments, -C(O)NHR1 is attached to the phenyl ring at a position pαrα to cyclopropylidene. Attorney Docket No. 8493-000092/WO/POA
In illustrative embodiments, the groups R1, R2, R6', R7', R8, R9 and R10 are selected to have the same combination of substituents as those of Compounds a7-01 through al2-04. That is, Compounds c7-01 through cl2-04 are like a7-01 through al2-04, except the former have pyrimidine where the latter have thiazole.
[0112] In one embodiment, the invention provides a compound of Formula (I-d) and a pharmaceutically acceptable salt thereof:
Figure imgf000065_0001
wherein Cy1, R1, R2, R3 and R4 are as defined above for various aspects of Formula (I).
[0113] In an embodiment of Formula (I-d), Cy1 is cyclopropylidene; and R4 is independently selected from the group consisting of H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, N,N-(Ci_io alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, N,N-(Ci_io alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-10 alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-10 alkyl) sulphamoyl and NjN-(C1-1O alkyl)2sulphamoyl, wherein each R4 is optionally substituted by one or more B where such an optional substitution is chemically feasible. Νon-limiting examples of such compounds include the following compounds and pharmaceutically acceptable salts thereof:
Figure imgf000065_0002
wherein R1 and R2 are as defined above; and R11, R12 and R13 are independently selected from the functional groups of R4 defined herein. Attorney Docket No. 8493-000092/WO/POA
[0114] In an embodiment of Formula (I-d), Cy1 is cyclopropylidene; and one and only one R4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a fused ring and R4 is optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. Compounds of this embodiment include, but are not limited to, the following formulae:
Figure imgf000066_0001
where the groups R6', R7', R8, R9, and R10 are independently selected from H and the functional groups of R5 defined herein. In various embodiments, m is 0; both groups R4 are H; and/or - CONH-R1 is attached to the thiophene ring position adjacent the S atom. In illustrative embodiments, the groups R1, R6', R7', R8, R9 and R10 are selected to have the same combination of substituents given in the table for each of Compounds al-01 to al-200.
[0115] In an embodiment of Formula (I-d), Cy1 is cyclopropylidene; and one and only one R4 is aryl, cycloalkyl or heterocyclyl, wherein aryl, cycloalkyl or heterocyclyl is a monocyclic ring optionally further substituted by one or more R5 where such an optional substitution is chemically feasible; and R5 is as defined above. Compounds of this embodiment include, but are not limited to, the following formulae: Attorney Docket No. 8493-000092/WO/POA
Figure imgf000067_0001
where the groups R6', R7', R8, R9, and R10 are independently selected from H and the functional groups of R5 defined herein. In particular embodiments, m is 0; both groups R4 are H; and/or - CONH-R1 is attached to the thiophene ring position adjacent the S atom. In various embodiments, the groups R1, R6', R7', R8, R9 and R10 are selected to have the same combination of substituents as those of Compounds a7-01 through al2-04. That is, Compounds d7-01 through dl2-04 are like a7-01 through al2-04, except the former have pyrimidine and thiophene where the latter have thiazole and phenyl, respectively.
[0116] In one embodiment, the invention provides a compound selected from the group consisting of Formulae (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (M), (I-m), (I-n), (I-o), (I-p), (I-q), and (I-r), and a pharmaceutically acceptable salt thereof:
(I-f)
Figure imgf000067_0002
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000068_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000069_0001
wherein Cy1, R1, R2, R3 and R4 are as defined above for various aspects of Formula (I).
[0117] Non-limiting examples of such compounds include the following compounds and pharmaceutically acceptable salts thereof:
Figure imgf000069_0002
Compound e-01 Compound e-03
Figure imgf000069_0004
Figure imgf000069_0003
Compound e-04 Compound e-06
Figure imgf000069_0007
Figure imgf000069_0005
Figure imgf000069_0006
Compound e-07 Compound e-08 Compound e-09 Attorney Docket No. 8493-000092/WO/POA
Figure imgf000070_0001
Compound f-01 Compound f-03
Figure imgf000070_0004
Figure imgf000070_0002
Compound g-01 Compound g-02
Figure imgf000070_0005
Figure imgf000070_0003
Compound q-01
Figure imgf000070_0007
Figure imgf000070_0006
Compound q-04 Compound q-05 Compound q-06 Attorney Docket No. 8493-000092/WO/POA
Figure imgf000071_0001
Compound r-01 Compound r-02 Compound r-03
[0118] In yet another embodiment, the invention provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof:
Figure imgf000071_0002
(II) wherein Cy1, R1, R6 and R7 are as defined above. [0119] In particular embodiments, the variables are further exemplified as follows:
Cy1 is cyclopropylidene, cyclopentylidene or tetrahydropyran-4,4-diylidene; R1 is hydroxyl or phenyl substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, wherein R1 is optionally further substituted with one or more groups selected from amino, halo, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
R6 is Ci_3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy, C1-3 alkanoyl, imidazopyridinyl or pyridinyl, wherein if R6 is not imidazopyridinyl or pyridinyl, R6 is optionally substituted by one or more B where such an optional substitution is chemically feasible, and if R6 is imidazopyridinyl or pyridinyl, R6 is optionally further substituted by one or more R5; R7 is Ci_3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 alkoxy or C1-3 alkanoyl;
R5 is independently selected from the group consisting of halo, nitro, cyano, hydroxyl, oxo, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkanoyl, Ci_6 alkanoyloxy, N-(C1-6 alkyl)amino, NN-(C1-6 alkyl)2amino, C1-6 alkanoylamino, N-(C1-6 alkyl)carbamoyl, NN-(C1-6 alkyl)2carbamoyl, C1-6 alkyl-S(O)a wherein a is 0, 1 or 2, C1-6 alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-6 alkyl)sulphamoyl, N,N-(C1-6 alkyl)2sulphamoyl, Attorney Docket No. 8493-000092/WO/POA
aryl, aryloxy, arylthio, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyl(C=O)-, heterocyclyloxy and heterocyclylthio; wherein R5 is optionally substituted by one or more D where such an optional substitution is chemically feasible;
B and D are independently selected from halo, nitro, cyano, hydroxyl, oxo, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 alkoxy, Ci_6 alkanoyl, Ci_6 alkanoyloxy, N-(Cι-β alkyl)amino, N,N-(Cι-β alkyl)2amino, Ci_6 alkanoylamino, N-(Cι-β alkyl)carbamoyl, N,N- (C1-6 alkyl)2carbamoyl, Ci_6 alkyl-S(O)a wherein a is 0, 1 or 2, Ci_6 alkoxycarbonyl, N- (C1-6 alkyl)sulphamoyl, _V,_V-(C1-6 alkyl)2sulphamoyl, H2NS(O)2NH-, N-(Ci-6 alkyl)NHS(O)2NH-, _V,_V-(C1-6 alkyl)2ΝS(O)2ΝH-, aryl, aryloxy, arylthio, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyl(C=O)-, heterocyclyloxy and heterocyclylthio. [0120] Examples of such compounds include, but are not limited to:
Figure imgf000072_0001
and pharmaceutically acceptable salts thereof. Compound preparation
[0121] A compound of the present invention such as those of Formulae (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (1-1), (I-m), (I-n), (I-o), (I-p), (I-q), and (I-r) can be prepared according to the schemes described below, but it shall be appreciated that modifications of the illustrated process or other processes can also be used. Attorney Docket No. 8493-000092/WO/POA
Figure imgf000073_0001
[0122] Cycloalkylidene linked HDAC inhibitors can be synthesized according to Scheme 1, showing preparation of inhibitors 8a and 8b where Ar is phenyl and where Cy2 is a substituted thiazole. In Scheme 1, α-cyano-p-methylbenzoic acid ester 1 is reacted with dibromide 2 (q is an integer from 1 to 6) to form cyano intermediate 3a, which is in turn reacted with hydrogen sulfide to yield thioamide compound 4a. Thiazole intermediate 6 is prepared by reacting thioamide 4a with α-bromo carbonyl compound 5. Substituents R6 and R7 on intermediate 5 are selected from H and the functional groups of R4 defined herein and become the substituents on ring Cy2 of the inhibitors. Thiazole intermediate 6 is then reacted with 1,2-diamino aryl compound 7a to provide arylamide HDAC inhibitor 8a or with NH2OH to provide hydroxamate inhibitor 8b.
[0123] Scheme 1 can be genericized with respect to the group Ar of the HDAC inhibitors. In scheme 2, inhibitors 8' are synthesized from starting esters 1' by way of thioamide intermediate 4'.
Figure imgf000073_0002
[0124] Inhibitors with heterocycloalkylidene linkers Cy1 can be synthesized analogously to Schemes 1 and 2 by reaction of starting compounds 1 or 1' with a dibromoether 2' as in Scheme 3. Scheme 3 illustrates the synthesis when Ar in the inhibitor is a 1,4-substituted phenyl, with Cy1 taken as position 1. Attorney Docket No. 8493-000092/WO/POA
Scheme 3
Figure imgf000074_0001
Figure imgf000074_0003
Figure imgf000074_0002
[0125] In one embodiment, intermediate 5 is prepared containing a ring substituent at R' according to Scheme 4. A first synthetic route begins with the reaction of an aminopyridine b with a chlorodiketone a to make an acyl imidazopyridine c, which is brominated to bromoketone
5.
Scheme 4
Figure imgf000074_0004
[0126] A second route to bromoketone 5 is given in Scheme 5, where the imidazopyridine is formed first and is then acylated and brominated.
'
Figure imgf000074_0005
In Scheme 5, the imidazo ring is elaborated first, and then subjected to acylation to add the ketone side chain and group R4, both of which will become part of the thiazole in subsequent synthetic steps. In one sense, this affords more flexibility in the choices of R6 and R4 than does Attorney Docket No. 8493-000092/WO/POA
Scheme 4. At the same time, the reaction of aminopyridine b with chloroketone or chloroaldehyde d occurs under similar conditions as in Scheme 4, and is permissive of the same broad range of substituents R7, R8, R9, and R10 on the aminopyridine starting material b. [0127] Pyrimidine inhibitor compounds can be made as in Scheme 6.
Scheme 6
Figure imgf000075_0001
Cyanocycloalkylidene 3a is converted to urea compound 4a and reacted with aminoketone 5 to give ester 6. Ester 6 is converted to arylamide 8a or to hydroxamate 8b.
[0128] Alternatively, pyrimidine compounds can be synthesized according to Scheme 7, where intermediate 6 is alkylated to form cycloalkylidene 3 before reaction to the hydroxamate or arylamide. Alternatively, intermediate 6 of Scheme 7 can be alkylated as in Scheme 3 to form a heterocycloalkylidene analog of intermediate 3 (not shown).
Scheme 7
Figure imgf000075_0002
[0129] The compounds of the present invention inhibit histone deacetylase and are useful to treat or ameliorate diseases mediated directly or indirectly by HDAC. Therefore, another aspect Attorney Docket No. 8493-000092/WO/POA
of the present invention is to provide a pharmaceutical composition comprising an effective amount of one or more compounds as described above.
[0130] In one embodiment of the invention, a pharmaceutical composition is provided comprising, in addition to one or more compounds described herein, at least one pharmaceutically-acceptable diluent, adjuvant, excipient, or carrier. The composition can take any suitable form for the desired route of administration. Where the composition is to be administered orally, any suitable orally deliverable dosage form can be used, including without limitation tablets, capsules (solid- or liquid-filled), powders, granules, syrups and other liquids, elixirs, inhalants, troches, lozenges, and solutions. Injectable compositions or iv infusions are also provided in the form of solutions, suspensions, and emulsions.
[0131] A pharmaceutical composition according to the present invention may contain one or more additional therapeutic agents, for example, to increase the efficacy or decrease the side effects. In some embodiments, accordingly, a pharmaceutical composition further contains one or more additional therapeutic agents selected from active ingredients useful to treat or inhibit diseases mediated directly or indirectly by HDAC. Examples of such active ingredients are, without limitation, agents to treat or inhibit cancer, Huntington's disease, cystic fibrosis, liver fibrosis, renal fibrosis, pulmonary fibrosis, skin fibrosis, Rheumatoid arthritis, diabetes, stroke, amyotrophic lateral sclerosis, cardiac hypertrophy, heart failure or Alzheimer's disease.
[0132] In an embodiment, an additional therapeutic agent to be included is an anti-cancer agent. Examples of an anti-cancer agent include, but are not limited to, alkylating agents such as cyclophosphamide, dacarbazine, and cisplatin; antimetabolites such as methotrexate, mercaptopurine, thioguanine, fluorouracil, and cytarabine; plant alkaloids such as vinblastine, and paclitaxel; antitumor antibiotics such as doxorubicin, bleomycin, and mitomycin; hormones/antihormones such as prednisone, tamoxifen, and flutamide; other types of anticancer agents such as asparaginase, rituximab, trastuzumab, imatinib, retinoic acid and derivatives, colony- stimulating factors, amifostine, camptothecin, topotecan, thalidomide analogs such as lenalidomide, CDK inhibitor and other HDAC inhibitor such as histone deacetylase 1 inhibitors, histone deacetylase 2 inhibitors, histone deacetylase 3 inhibitors, histone deacetylase 4 inhibitors, histone deacetylase 5 inhibitors, histone deacetylase 6 inhibitors, histone deacetylase 7 inhibitors, histone deacetylase 8 inhibitors, histone deacetylase 9 inhibitors, histone deacetylase 10 inhibitors, and histone deacetylase 11 inhibitors. Attorney Docket No. 8493-000092/WO/POA
[0133] Yet another aspect of the present invention is to provide a method of inhibiting or treating diseases arising from abnormal cell proliferation and/or differentiation in animal, comprising administering to said animal a therapeutically effective amount of one or more compounds according to the present invention. In one embodiment, the method of inhibiting or treating disease comprises administering to an animal a composition comprising an effective amount of one or more compounds of the invention and a pharmaceutically-acceptable carrier. The composition to be administered may further contain a therapeutic agent such as anti-cancer agent.
[0134] A method of the present invention is particularly suitable for use with humans, but may be used with other animals, particularly mammals, such as, for example, non-human primates, companion animals, farm animals, laboratory animals, and wild and zoo animals.
[0135] A method of the present invention is particularly useful to treat diseases mediated directly or indirectly by HDAC since the compounds of the present invention have inhibitory activity against those molecules. In some embodiments, therefore, a method of the present invention is used in inhibiting or treating HDAC-mediated diseases. Examples of such disease include, but are not limited to, cell proliferative diseases such as cancer, autosomal dominant disorders such as Huntington's disease, genetic related metabolic disorder such as cystic fibrosis, fibrosis such as liver fibrosis, renal fibrosis, pulmonary fibrosis and skin fibrosis, autoimmune diseases such as Rheumatoid arthritis, diabetes, acute and chronic neurological diseases such as stroke, hypertrophy such as cardiac hypertrophy, heart failure including congestive heart failure, amyotrophic lateral sclerosis, and Alzheimer's disease.
[0136] In an embodiment, a method according to the present invention is applied to a patient with cancer, cystic fibrosis, or pulmonary fibrosis. In some embodiments, a method using a compound according to the present invention is used to treat or inhibit a cancer selected from bladder cancer, breast cancer, colon and rectal cancer, endometrial cancer, kidney (renal cell) cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, skin cancer (non-melanoma), and thyroid cancer.
EXAMPLES
[0137] The following examples are merely illustrative, and do not limit this disclosure in any way. Attorney Docket No. 8493-000092/WO/POA
EXAMPLE 1
[0138] N-(2-amino-phenyl)-4-{ l-[4-(2-methyl-imidazo[l,2-α]pyridin-3-yl)-thiazol-2-yl]- cyclopropyl } -benzamide
Figure imgf000078_0001
a1-29) [0139] Preparation of Intermediate (hereinafter "Int") 6: Int-1 (1.92g, 11.01 mmol) and 1,2-dibromoethane (4.76 rnL, 55.04 mmol) were combined in tetrahydrofuran (THF) (40 mL) and cooled down to 0 0C. To this solution, potassium bis(trimethylsilyl)-amide (0.5M, 48.3 mL, 24.21 mmol) was added in a period of 15 minutes and then warmed up to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase were washed with aqueous solution of NaHCO3 and brine, dried with MgSO4 and evaporated under vacuum. The crude product was purified by chromatography on silica gel (25% EtOAc/hexanes) to afford Int-2 (1.55g, 7.71 mmol, 70.33%). To a solution of Int-2 in MeOH (50 mL) was added Et3N (2.5 mL). H2S was bubbled into the solution. The reaction vessel was stirred at room temperature for 4 days. The reaction mixture was evaporated and purified by silica gel chromatography (33% EtOAc/hexanes) to Int-3 (1.23g, 5.22 mmol, 67%). l-(2-methyl-imidazo[l,2-α]pyridine-3-yl)-ethanone (0.25g, 1.44 mmol) was dissolved in a mixture of HBr/AcOH (33%) (2 mL) and AcOH (4 mL). A solution of Br2 (0.1 mL) in CHCl3 (3 mL) was added at room temperature. After 10 minutes of stirring, the reaction mixture was completed. The solids were filtered out, dissolved in EtOAc, washed out with aqueous NaHCO3, Na2S2O3, dried with MgSO4 and evaporated in vacuum to afford Int-4 (0.32g, 1.26 mmol, 86%). Int-4 (0.1 Ig, 0.42 mmol) and Int-3 (O.lOg, 0.42 mmol) were dissolved in EtOH (10 mL) and heated to reflux under stirring for 20 minutes. The reaction mixture was evaporated under vacuum. The crude Int-5 (0.15g) was used in the next step without further purification. Int-5 (0.15g, 0.38 mmol) was dissolved in MeOH (6 mL) and treated with an aqueous solution of IN NaOH (2 mL). The reaction mixture was stirred for 2 hours and then IN aqueous HCl was Attorney Docket No. 8493-000092/WO/POA
added until reaching pH 5. The suspension was filtered out to have Int-6 (0.14g, 0.36 mmol,
94%). [0140] Preparation of Compound 7: A solution of Int-6 (O.lOg, 0.26 mmol), 1,2- phenylenediamine (57.67 mg, 0.53 mmol), hydroxybenzotriazole (HOBt) (36.03 mg, 0.26 mmol), EDC (102 mg, 0.53 mmol), in JV-methyl-2-pyrrolidone (NMP) (5 mL) was stirred for 30 minutes and then JV,./V-diisopropylethylamine (DIPEA) (74μL) was added and the mixture was stirred for
2 hours. Water was added to precipitate the product. The solids were filtered and washed with more water, and dried on a filter to afford Compound 7 (O.lg, 0.21 mmol, 80%). 1H-NMR
(dimethyl sulfoxide (DMSO)) δ: 8.90 (d, J=6.8Hz, IH), 8.04 (d, J=8.4Hz, 2H), 7.71 (d, J=8Hz, 2H), 7.53-7.50 (m, 3H), 7.34 (t, J=7.2Hz, IH), 7.21 (d, J=7.6Hz, IH), 7.09 (t, J=7.2Hz, IH),
6.98-6.91 (m, 2H), 6.78 (t, J=8.4Hz, IH), 2.55 (s, 3H), 1.91-1.88 (m,2H), 1.61-1.58 (m, 2H). MS m/z: 466 (MH+).
EXAMPLE 2
[0141] N-hydroxy-4-{ l-[4-(2-methyl-imidazo[l,2-α]pyridin-3-yl)-thiazol-2-yl]- cyclopropylj-benzamide
CK ? . ™".EDIPA
Figure imgf000079_0001
6 8
Example 2 (Compound a1-25)
[0142] Int-6 of Example 1 (0.24g, 0.64 mmol), PyBOP (0.39g, 0.76 mmol), NH2OTBS (0.37g, 2.56 mmol) and DIPEA (0.22 mL, 1.28 mmol) were mixed in NMP (5 mL) and stirred for 2 hours at room temperature. After the reaction was completed, IN HCl 1 mL was added to the reaction mixture and stirred overnight. Once the hydrolysis was done, preparative high performance liquid chromatography (HPLC) purification was performed to obtain Compound 8. 1H-NMR (DMSO) δ: 11.22 (s, IH), 8.82 (d, J=6.8Hz,lH), 8.44 (s, IH), 7.76 (d, J=8.2Hz, 2H), 7.20-7.12 (m, 3H), 7.49 (d, J=8.8Hz, IH), 7.23 (t, J=6.8, IH), 6.91 (t, J=6.1Hz, IH), 2.46 (s, 3H), 1.78-1.72 (m, 2H), 1.53-1.47 (m, 2H). m/z = 390.12 EXAMPLE 3
[0143] 4-[l-(5-Acetyl-4-methyl-thiazol-2-yl)-cyclopropyl]-N-(2-amino-phenyl)-benzamide Attorney Docket No. 8493-000092/WO/POA
Figure imgf000080_0001
[0144] 3-Chloro-pentane-2,-4-dione (24, 0.37 mmol) and Int-1 (50 mg, 0.3719 mmol) were dissolved in MeOH (1 rnL) and heated in the microwave to 12O0C for 30 minutes. The reaction mixture was evaporated and extracted with water and EtOAc. The organic phase were dried with MgSO4 and evaporated under vacuum. The crude product Int-2 was used without further purification for ester hydrolysis. The same procedure to get Int-6 and Int-7 of Example 1 was used to synthesize Compound 4 from Int-2: 1H-NMR (MeOD) δ: 8.30 (d, J=8.0Hz, 2H), 7.64 (d, J=8.4Hz, 2H), 7.20 (d, J=8.0Hz, IH), 7.08 (t, J=7.96Hz, IH), 6.92 (d, J=7.6Hz, IH), 6.78 (t, J=7.4Hz, IH), 2.62 (s, 3H), 2.41 (s, 3H), 1.88-1.84 (m,2H), 1.58-1.54 (m, 2H). MS m/r. 392 (MH+). EXAMPLE 4
[0145] 2-( 1 -(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)-N,N-4-trimethylthiazole-5- carboxamide
Figure imgf000080_0002
Example 4 (Compound aO-46)
[0146] Int-1 (200 mg, 0.85 mmol) and 2-chloro-Λ/,N-dimethyl-3-oxo-butyramide 2-chloro- JV,./V-dimethyl-3-oxo-butyramide (0.46 mL, 1.70 mmol) were dissolved in MeOH (3 mL), and DIPEA (0.3 mL, 1.70 mmol) was added. The mixture was heated in the microwave for 30 minutes at 9O0C. The reaction mixture was evaporated and extracted with water and EtOAc and saturated aqueous solution of NaHCO3. The organic phase was dried with MgSO4 and evaporated under vacuum. The crude product Int-2 was used without further purification for hydrolysis. The same procedure to get Int-6 and Int-7 of Example 1 was used to synthesize Attorney Docket No. 8493-000092/WO/POA
Compound 4 from Int-2. 1H-NMR (MeOD) δ: 8.05 (d, J=6.4Hz, 2H), 7.62 (d, J=8.0Hz, 2H), 7.10 (d, J=7.6Hz, IH), 7.05 (t, J=7.6Hz, IH), 6.95 (d, J=7.6Hz, IH), 6.78 (t, J=7.2Hz, IH), 3.05 (s, 6H), 2.32 (s, 3H), 1.90-1.86 (m,2H), 1.62-1.58 (m, 2H). MS m/z: 421 (MH+). EXAMPLE 5 [0147] N-(2-Amino-phenyl)-4-[l-(4-pyridin-3-yl-thiazol-2-yl)-cyclopropyl]-benzamide
a10-02)
Figure imgf000081_0001
1
[0148] Int-2 (0.2g, 16.51 mmol) was dissolved in a mixture of HBr/AcOH 33% (2 mL) and AcOH (4 mL). 93.3μL Br2 (1.1 equivalents (eq)) in chloroform (3 mL) was added slowly to the solution at room temperature. After 5 minutes the crystals in suspension were filtered out and worked out with water and EtOAc. The organic phase was dried with MgSO4 and evaporated under vacuum. The crude product was used without further purification for next step. The procedure to synthesize Int-5 of Example 1 was followed to synthesize Int-4 but using Int-3. The same procedure to get Int-6 and Int-7 of Example 1 was used to synthesize Compound 6 from Int-4. 1H-NMR (DMSO) δ: 9.66 (s, IH), 9.08 (s, IH), 8.48 (m, IH), 8.20 (d, J=8.4Hz, IH), 7.95 (s, IH), 7.92 (d, J=8.0Hz, 2H), 7.60 (d, J=8.4Hz, 2H), 7.40-7.44 (m, IH), 7.13 (d, J=7.6Hz, IH), 6.92 (t, J=7.20Hz,lH), 6.72 (d, J=7.6Hz IH), 6.55 (t, J=7.2Hz, IH), 4.85 (s, IH), 1.79-1.75 (m,2H), 1.52-1.48 (m, 2H). MS m/z: 413 (MH+). EXAMPLES 6 AND 7 [0149] Example 6: N-(2-Amino-phenyl)-4-[l-(4-pyridin-3-yl-thiazol-2-yl)-cyclopentyl]- benzamide
[0150] Example 7: N-(2-Amino-phenyl)-4-{ l-[4-(2-methyl-imidazo[l,2-α]pyridin-3-yl)- thiazol-2-yl] -cyclopentyl } -benzamide Attorney Docket No. 8493-000092/WO/POA
Figure imgf000082_0001
Example 6 (Compound a'10-02 (q=3)) Example 7 (Compound a'1-29 (q=3))
[0151] The same procedure to get Int-2 and Int-3 of Example 1 was used to synthesize Int-3. Then the procedure to get Int-5 of Example 1 was followed for the synthesis of Int-4 and Int-7 but using 2-bromo-l-pyridin-3-yl-ethanone and 2-bromo-l-(2-methyl-imidazo[l,2-α]pyridin-3- yl)-ethanone. Following the procedure to get Int-6 of Example 1, Int-5 and Int-8 were synthesized.
[0152] Preparation of Compounds 6 and 9: The same procedure to get Int-6 and Compound 7 of Example 1 was used to synthesize Compound 6 and Compound 9 from Int-5 and Int-8, respectively. Compound 6: 1H-NMR (DMSO) δ: 9.58 (s, IH), 8.82 (d, J=6.8Hz, IH), 7.79 (d, J=8.4Hz, 2H), 7.75 (d, J=8.0Hz 2H), 7.50 (d, J=7.6Hz, IH), 7.32 (t, J=7.0Hz, IH), 7.12 (d, =7.2Hz, IH), 6.98-6.90 (m, 2H), 6.74 (d, J=7.6Hz, IH), 6.52 (t, J=7.2Hz, IH), 4.80 (s, 2H), 2.82- 2.74 (m, 2H), 2.34-2.30 (m, 2h), 1.84-1.78 (m, 4H). MS m/z: 494 (MH+). Compound 9: 1H- NMR (DMSO) δ: 9.60 (s, IH), 9.18 (s, IH), 8.48 (d, J=8.0Hz, IH), 8.23 (d, J=8.4Hz, IH), 8.18 (s, IH), 7.95 (d, J=8.4Hz, 2H), 7.59 (d, J=8.2, 2H), 7.43 (t, J=7.6Hz, IH), 7.18 (d, J=8.0Hz, IH), 6.95 (t, J=7.2Hz, IH), 6.78 (d, J=7.6Hz, IH), 6.49 (t, J=7.2Hz, IH), 2.72-2.80 (m, 2H), 2.32-2.20 (m, 2H), 1.80-1.75 (m, 4H), 1.80-1.75 (m, 4H). MS m/z: 441 (MH+). Attorney Docket No. 8493-000092/WO/POA
EXAMPLES 8 AND 9
[0153] Example 8: N-(2-Amino-phenyl)-4-[4-(4-pyridin-3-yl-thiazol-2-yl)-tetrahydro-pyran- 4-yl]-benzamide
[0154] Example 9: N-(2-Amino-phenyl)-4-{4-[4-(2-methyl-imidazo[l,2-α]pyridin-3-yl)- thiazol-2-yl] -tetrahydro-pyran-4-yl } -benzamide
Figure imgf000083_0001
[0155] Preparation of Int-3: The procedure to get Int-2 of Example 1 was followed to synthesize Int-2 and Int-3 but using l-bromo-2-(2-bromo-ethoxy)-ethane. [0156] Preparation of Compounds 6 and 9: The procedure to get Int-5 of Example 1 was followed for the synthesis of Int-4 and Int-7 but using 2-bromo-l-pyridin-3-yl-ethanone and 2- bromo-l-(2-methyl-imidazo[l,2-α]pyridin-3-yl)-ethanone. The same procedure to get Int-6 and Compound 7 of Example 1 was used to synthesize Compound 6 and Compound 9 from Int-4 and Int-7, respectively. Compound 6: 1H-NMR (DMSO) δ: 9.58 (s, IH), 9.18 (s, IH), 8.54 (d, J=8.0Hz, IH), 8.28 (d, J=8.4Hz, IH), 8.21 (s, IH), 7.9 (d, J=8.4Hz, 2H), 7.6 (d, J=8.0, 2H), 7.42 (t, J=7.4Hz, IH), 7.10 (d, J=7.0Hz, IH), 6.95 (t, J=7.2Hz, IH), 6.70 (d, J=7.6Hz, IH), 6.55 (t, J=7.2Hz, IH), 4.82 (s, 2H), 3.78-3.65 (m, 2H), 3.68-3.60 (m, 2H), 2.70-2.62 (m, 2H), 2.42-2.38 (m, 2H). MS m/r. 457 (MH+). Compound 9: 1H-NMR (DMSO) δ: 9.60 (s, IH), 8.84 (d, J=6.4Hz, Attorney Docket No. 8493-000092/WO/POA
IH), 7.96 (d, J=8.2Hz, 2H), 7.82 (s, IH), 7.65 (d, J=8.0Hz, 2H), 7.56 (d, J=7.8Hz, IH), 7.32 (t, =7.6Hz, IH), 7.18 (d, J=7.0Hz, IH), 7.0-6.92 (m, 2H), 6.76 (d, J=7.0Hz, IH), 6.58 (t, J=7.2Hz, IH), 4.88 (s, 2H), 3.75-3.65 (m, 4h), 2.78-2.65 (m, 2H), 2.58-2.50 (m, 2H). MS m/z: 510 (MH+). EXAMPLE 10
[0157] 2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)-/V-isopropylthiazole-4- carboxamide
Figure imgf000084_0001
Example 10 (Compound aO-45)
[0158] 3-Bromo-2-oxo-propionic acid (142 mg, 0.85 mmol) and Int-1 (100 mg, 0.4255 mmol) were dissolved in dimethylformamide (DMF). DIPEA (0.15 rnL, 0.84 mmol) was added and the whole mixture heated in microwave at 100 0C for 80 minutes. The reaction mixture was evaporated and extracted with EtOAc, water, and saturated aqueous solution of NaHCO3. The organic phase was dried with MgSO4 and evaporated under vacuum. The crude product Int-2 was used without further purification for ester hydrolysis. p-TsOH was added in excess to a solution of Int-2 (100 mg, 0.31 mmol) in MeOH and heated in microwave for 30 minutes at 80 0C. The reaction mixture was evaporated and extracted with EtOAc, water and a saturated aqueous solution of NaHCO3. The organic phase was dried with MgSO4 and evaporated to yield Int-3. A solution of Int-3 (0.2g, 0.85 mmol), isopropylamine (O.lg, 1.70 mmol), HOBt (0.32g, 0.85), and DIPEA (0.28 mL, 1.70 mmol) were dissolved in DMF (3 mL) and stirred at room temperature for 2 hours. The reaction mixture was crushed out with water and saturated solution of NaHCO3 to the solution to have pure Int-4. This compound was used without further purification for next step. The same procedure to get Int-6 and Compound 7 of Example 1 was used to synthesize Compound 6 from Int-4. 1H-NMR (MeOD) δ: 8.03 (d, J=6.4Hz, 2H), 7.91 (s, IH), 7.64 (d, J=8.0Hz, 2H), 7.25 (d, J=8.0Hz, IH), 7.16 (t, J=7.6Hz, IH), 7.02 (d, J=7.2Hz, IH), 6.93 (t, J=7.6Hz, IH), 1.88-1.82 (m,2H), 1.59-1.53 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H). MS m/r. 421 (MH+). Attorney Docket No. 8493-000092/WO/POA
EXAMPLE Il
[0159] N-(2-amino-phenyl)-4-[l-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-cyclopropyl]- benzamide
Figure imgf000085_0001
[0160] 2-Chloro-cyclohexanone (0.5 rnL, 8.52 mmol) and Int-1 (0.5g, 2.13 mmol) were dissolved in DMF and (0.72 rnL, 4.26 mmol) of DIPEA was added. The whole mixture heated in microwave at 120 0C for 10 minutes. The reaction mixture was evaporated and extracted with EtOAc, water, and saturated aqueous solution of NaHCO3. The organic phase was dried with MgSO4 and evaporated under vacuum. The crude product Int-2 was used without further purification for dehydration. The same procedures to get Int-3 of Example 3 and Int-6 and Compound 7 of Example 1 were used to synthesize Compound 5 from Int-2. 1H-NMR (MeOD) δ: 7.95 (d, J=8.2Hz, 2H), 7.50 (d,J=8.4Hz, 2H), 7.2 (d, J=7.6Hz, IH), 7.10 (d, J=7.2Hz, IH), 7.88 (d, J=7.2Hz, IH), 6.78 (t, J=7.4Hz, IH), 2.70-2.65 (m, 4H), 1.70-1.65 (m, 4H), 1.50-1.42 (m, 2H). MS m/r. 390 (MH+). EXAMPLES 12, 13 AND 14
[0161] Example 12: Ethyl-2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
[0162] Example 13: N-(2-amino-phenyl)-4-[l-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2- yl)-cyclopropyl] -benzamide [0163] Example 14: te/t-butyl 2-(l-(4-(2-aminophenylcarbamoyl)phenyl) cyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate Attorney Docket No. 8493-000092/WO/POA
HATU
Figure imgf000086_0001
Example 13 (Compound aO-48) Example 14 (Compound aO-57)
[0164] Preparation of Compound 5: 3-Bromo-4-oxo-piperidine-l-carboxylic acid ethyl ester (1.06 g, 4.24 mmol) and Int-1 (500 mg, 2.12 mmol) were dissolved in DMF. DIPEA (0.72 rnL, 4.24 mmol) was added and the whole mixture heated in microwave at 75 0C for 60 minutes. The reaction mixture was extracted with EtOAc, water, and saturated aqueous solution of NaHCO3. The organic phase were dried with MgSO4 and evaporated under vacuum to yield Int-2. The procedures to get Int-3 of Example 3 and Int-6 and Compound 7 of Example 1 were followed in order to synthesize Int-3, Int-4 and Compound 5, respectively. Compound 5: 1H- NMR (DMSO) δ: 9.62 (s, IH), 7.95 (d, J=6.4Hz, 2H), 7.45 (d, J=8.4Hz, 2H), 7.05 (d, J=7.6Hz, IH), 6.92 (t, J=7.2Hz, IH), 6.65 (d, J=7.6Hz, IH), 6.52 (t, J=7.2Hz, IH), 4.82 (s, 2H), 4.42 (s, 2H), 4.02-3.98 (m, 2H), 3.62-3.58 (m, 2H), 2.66-2.60 (m, 2H), 2.58-2.52 (m, 2H), 1.39-1.32 (m, 2H), 1.08-1.05 (m, 2H). MS m/z: 463 (MH+).
[0165] Preparation of Compound 6: Int-5 (0.2 g, 0.43 mmol) was added in MeOH (3 mL) and treated with an aqueous solution of 3.5N NaOH (1 mL). The reaction mixture was stirred overnight at 50 0C and then IN of aqueous HCl was added until reaching a neutral pH. The reaction mixture was extracted with EtOAc and water. The organic phase dried over MgSO4 and evaporated. Further purification was done to have Compound 6. 1H-NMR (DMSO) δ: 9.62 (s, IH), 8.15 (s, IH), 7.92 (d, J=8.4Hz, 2H), 7.48 (d, J=8.2Hz, 2H), 7.10 (d, J=7.6Hz, IH), 6.90 (t, J=7.0Hz, IH), 6.72 (d, J=7.2Hz, IH), 6.55 (t, J=7.0Hz, IH), 4.85 (s, 2H), 3.70-3.66 (m, 2H), Attorney Docket No. 8493-000092/WO/POA
2.90-2.85 (m, 2H), 2.55-2.50 (m, 2H), 1.55-1.50 (m, 2H), 1.35-1.32 (m, 2H). MS m/z: 391 (MH+).
[0166] Preparation of Compound 9: Int-7 (0.2 mg, 0.52 mmol) was dissolved in MeOH and treated with a 2.5 equivalents of an aqueous 3.5N solution of NaOH. The reaction mixture were stirred overnight at 50 0C and then evaporated to be use on next step without further purification. Int-8 (0.15g, 0.5 mmol) was dissolved in MeOH and άi-tert-butyX dicarbonate (BOC2O) (0.543 mg, 2.5 mmol) at 0 0C and stirred for 2 hours until the reaction was completed. The reaction mixture was evaporated and extracted with EtOAc and water. The organic phase was evaporated and used without further purification for the next step. Procedure to get Compound 7 of Example 1 was followed in order to get Compound 9. 1H-NMR (MeOD) δ: 7.96 (d, J=8.4Hz, 2H), 7.56 (d, J=8.2Hz, 2H), 7.17 (d, J=7.0Hz, IH), 7.06 (t, J=7.6Hz, IH), 6.89 (d, J=7.6Hz, IH), 6.76 (t, J=7.0Hz, IH), 4.52-4.49 (m, 2H), 3.72-3.65 (m, 2H), 2.79-2.75 (m, 2H), 1.72-1.68 (m, 2H), 1.50-1.45 (m, 2H), 1.44 (s, 9H). MS m/z: 491 (MH+). EXAMPLE 15
[0167] N-(2-amino-cyclohexa- 1 ,5-dienyl)-4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)- benzamide
Figure imgf000087_0001
Example 15 (Compound a"0-10)
[0168] The same procedure to synthesize Int-5 of Example 10 was followed to synthesize Int-2 but using chloro-acetaldehyde in methanol. The same procedure to get Int-6 and Compound 7 of Example 1 was used to synthesize Compound 4. 1H-NMR (MeOD) δ: 9.62 (s, IH), 7.95 (d, J=8.4Hz, 2H), 7.75 (d, J=7.6Hz, IH), 7.63 (d, J=7.2Hz, IH), 7.52 (d, J=8.4Hz, 2H), 7.05 (d, J=7.6Hz, IH), 6.95 (t, J=7.2Hz, IH), 6.78 (d, J=7.6Hz, IH), 6.58 (t, J=7.2Hz, IH), 3.80- 3.72 (m, 2H), 3.50-3.45 (m, 2H), 2.64-2.60 (m, 2H), 2.40-2.32 (m, 2H). MS m/z: 380 (MH+). EXAMPLE 16
[0169] N-(2-aminophenyl)-4-(l-(4-methylthiazol-2-yl)cyclopropyl)benzamide Attorney Docket No. 8493-000092/WO/POA
Figure imgf000088_0001
Example 16 (Compound aO-111 )
[0170] Similar procedure from Example 1 was followed to obtain the title compound using l-bromopropan-2-one. MS found for C20Hi9N3OS as (M+H)+ 350.19. 1U NMR (400MHz, dmso-dβ): δ:9.65 (s, IH), 7.95 (d, / =6.4Hz, 2H), 7.53 (d, / =7.6Hz, 2H), 7.13 (d, / =7.2Hz, IH), 6.97-6.92 (m, 2H), 6.74 (d, / =8.4Hz, IH), 6.57 (d, / =6.8Hz, IH), 4.88 (s, 2H), 2.26 (s, 3H), 1.62-1.60 (m, 2H), 1.42-1.40 (m, 2H). EXAMPLE 17
[0171] (5)-4-(l-(5-(2-amino-3-methylbutanoyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2- yl)cyclopropyl)-/V-(2-aminophenyl)benzamide
Figure imgf000088_0002
-| Q Example 17 (Compound aO-55)
[0172] To a solution of 4-[l-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-cyclopropyl]- benzoic acid (100 mg, 0.333 mmol) in MeOH (3 mL), tert-Butoxycarbonyl-L-valine N- hydroxysuccinimide ester (Boc- VAL-OSu) (1.0 eq) was added and heated at reflux for 2 hours. After reaction was completed it was extracted with EtOAc. The organic phase was dried and
15 evaporated.
[0173] 0-(7-azabenzotriazol-l-yl)-ΛWΛ^Λf'-tetramethyluronium hexafluorophosphate
(HATU) coupling was carried out following the same procedures from Example 1. The resulting compound was dissolved in IN HCl and stirred for 1 hour. The resulting mixture was evaporated and purified by reverse phase chromatography to afford title compound. MS found for
20 C27H3IN5O2S as (M+H)+ 490.49. 1H NMR (400MHz, dmso-d6): δ:9.64 (s, IH), 7.95 (d, / =8.4Hz, 2H), 7.53 (d, / =8.4Hz, 2H), 7.13 (d, / =7.2Hz, IH), 6.96-6.92 (m, IH), 6.75 (d, / =8.0Hz, IH), 6.56 (t, / =6.4Hz, IH), 4.86 (s, 2H), 4.73-4.61 (m, 2H), 4.44-4.40 (m, IH), 3.82-3.49 (m, 3H), 1.59-1.58 (m, 2H), 1.42-1.41 (m, 2H), 0.86 (d, J=6.8Hz, 3H), 0.78 (d, / =6.8Hz, 3H), 0.75-0.73 (m, 2H). Attorney Docket No. 8493-000092/WO/POA
EXAMPLE 18
[0174] N-(2-aminophenyl)-4-(4-(4-(6-chloropyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000089_0001
Example 18 (Compound a" 10-07)
[0175] Similar procedure from Example 15 was followed to obtain the title compound using 2-bromo-l-(5-chloropyridin-3-yl)ethanone. MS found for C26H23ClN4O2S as (M+H)+ 491.35. 1H NMR (400MHz, dmso-d6): δ:8.94 (d, / =2.4Hz, IH), 8.34 (dd, / =8.4,6.0Hz, IH), 7.97-7.93 (m, 4H), 7.61 (d, / =8.8Hz, 2H), 7.50 (d, / =8.8Hz, IH), 7.15 (d, / =8.0Hz, IH), 7.07-7.02 (m, IH), 6.86 (t, / =6.4Hz, IH), 6.76-6.71 (m, IH), 4.82 (s, 2H), 3.91-3.86 (m, 2H), 3.80-3.71 (m, 2H), 2.81-2.78 (m, 2H), 2.53-2.46 (m, 2H). EXAMPLE 19
[0176] N-(2-Amino-5-fluoro-phenyl)-4-[l-(4-pyridin-3-yl-thiazol-2-yl)-cyclopropyl]- benzamide:
Figure imgf000089_0002
Example 19 (Compound a10-03)
[0177] Similar procedure from Example 22 was followed to obtain the title compound using (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester. MS found for C24Hi9FN4OS as (M+H)+ 431.43. 1H NMR (400MHz, dmso-d6): δ:9.68 (s, IH), 9.09 (d, / =1.6Hz, IH), 8.49 (dd, / =4.8,3.2Hz, 1H),8.23-8.2O (m, IH), 8.01-7.97 (m, 3H), 7.63 (dd, / =6.4,1.6Hz, 2H), 7.44-7.41 (m, 2H), 7.14 (dd, / =8.8, 7.6Hz, IH), 6.83-6.72 (m, 2H), 4.83 (s. 2H), 1.78-1.75 (m, 2H), 1.52- 1.49 (m, 2H). Attorney Docket No. 8493-000092/WO/POA
EXAMPLE 20
[0178] N-(2-aminophenyl)-4-(4-(4-(6-(pyrrolidin-l-yl)pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000090_0001
5 [0179] Similar procedure from Example 34 was followed to obtain the title compound using pyrrolidine instead of 1-cyclopropyl-piperazine. MS found for C3OH3INsO2SaS (M+H)+ 526.36. 1H NMR (400MHz, dmso-d6): δ:9.53 (s, IH), 8.62 (dd, / =2.4,2.2Hz, IH), 7.93 (dd, / =8.8,6.4Hz, IH), 7.88 (d, / =8.4Hz, 2H), 7.69 (s, IH), 7.53 (d, / =8.4Hz, 2H), 7.07 (dd, / =7.6,6.8Hz, IH), 6.90-6.86 (m, IH), 6.69 (dd, / =8.0,6.8Hz, IH), 6.53-6.49 (m, IH), 6.43 (d, / =8.0Hz, IH), 4.81 10 (s, 2H), 3.72-3.68 (m, 2H), 3.62-3.57 (m, 2H), 3.37-3.33 (m, 4H), 2.60-2.59 (m, 2H), 2.39-2.33 (m, 2H), 1.90-1.87 (m, 4H). EXAMPLE 21
[0180] N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-yl)tetrahydropyran-4-yl)benzamide
Figure imgf000090_0002
-| 5 Example 21 (Compound a"0-61 )
[0181] Similar procedure from Example 29 was followed to obtain the title compound using (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester De-protection was carried out with a mixture of dichloromethane/trifluoro acetic acid (DCM/TFA) (1:1) at room temperature. MS found for C29H30N4O2S2 as (M+H)+ 531.02. 1H NMR (400MHz, dmso-d6): δ:9.63 (s, IH), 20 7.90 (d, J=8.4Hz, 2H), 7.49 (d, / =8.4Hz, 2H), 7.39 (d, / =2.0Hz, IH), 7.28 (dd, / =4.8,4.0Hz, IH), 7.23 (dd, / =8.0,4.8Hz, IH), 7.16-7.15 (m, IH), 6.99-6.96 (m, IH), 6.73 (d, / =8.4Hz, IH), Attorney Docket No. 8493-000092/WO/POA
5.09 (s, 2H), 3.82-3.52 (m, 6H), 2.98-2.96 (m, 2H), 2.85-2.81 (m, 2H), 2.42 (s, 3H), 2.51-2.34 (m,
4H).
EXAMPLE 22
[0182] N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-(pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000091_0001
Example 22 (Compound a"10-04)
[0183] l-Pyridin-3-yl-ethanone (2g, 16.52 mmol) was dissolved in a mixture of AcOH (8 rnL) and HBr (4 rnL). After stirring for 20 minutes, Br2 (l.Oeq) in CHCl3 (3 mL) was added in a period of 5 minutes. When the reaction was completed, the solids were filtered out and washed with water and extracted with EtOAc. The organic phase was dried, evaporated, and used for next step. Compound 4-(4-thiocarbamoyl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (300 mg, 1.075 mmol) was dissolved in MeOH (7 mL) and 2-Bromo-l-pyridin-3-yl-ethanone (1.2 eq) was added and refluxed at 85 0C for 30 minutes. The reaction mixture was washed with saturated aqueous solution of NaHCO3 and then extracted with EtOAc. The organic phase was dried, evaporated and used for next step without any purification. Compound 4-[4-(4-pyridin-3-yl- thiazol-2-yl)-tetrahydro-pyran-4-yl] -benzoic acid methyl ester (200 mg, 0.52 mmol) was dissolved in MeOH and IN NaOH was added. After reaction was complete, the mixture was evaporated and acidified slowly with IN HCl. The formed solid was filtered out and used for next step without purification. Compound 4-[4-(4-Pyridin-3-yl-thiazol-2-yl)-tetrahydro-pyran-4- yl]-benzoic acid HATU (171 mg, 1.1 eq), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert- butyl ester (136 mg, 1.1 eq), and DIPEA (0.14 mL, 2.0 eq) were dissolved in DMF and heated at 50 0C overnight. The reaction mixture was washed with water and extracted with EtOAc. The organic phase was dried, evaporated, and re-dissolved in a mixture of DCM and TFA (1:1). After stirring for 1 hour at room temperature the mixture was evaporated and purified by reverse phase chromatography to give Example 22. MS found for C30H26N4O2S2 as (M+H)+ 539.12. 1H NMR (400MHz, dmso-dβ): δ:9.64 (s, IH), 9.12 (d, / =1.6Hz, IH), 8.49 (dd, / =4.8,3.2Hz, IH), 8.26- Attorney Docket No. 8493-000092/WO/POA
8.23 (m, IH), 8.17 (s, IH), 7.92 (d, / =8.4Hz, 2H), 7.57 (d, / =8.8Hz, 2H), 7.43-7.28 (m, 2H), 7.27 (t, / =4.4Hz, IH), 7.22 (dd, / =8.4,6.1Hz, IH), 7.16-7.15 (m, IH), 6.97 (dd, / =5.2,1.6Hz, IH), 6.72 (d, / =8.4Hz, IH), 5.09 (s, 2H), 3.73-3.70 (m, 2H), 3.63-3.58 (m, 2H), 2.67-2.64 (m, 2H), 2.42-2.36 (m, 2H). EXAMPLE 23
[0184] N-(2-amino-5-fluorophenyl)-4-(4-(4-(pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000092_0001
Example 23 (Compound a"10-03)
[0185] Similar procedure from Example 9 was followed to obtain the title compound using (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester. MS found for C2OH2SFN4O2SaS (M+H)+ 475.45. 1H NMR (400MHz, dmso-d6): δ:9.58 (s, IH), 8.52 (dd, / =4.8,3.2Hz, IH), 8.29- 8.26 (m, 1H),8.19 (s, IH), 8.13 (s, IH), 7.91 (d, / =8.4Hz, 2H), 7.60 (d, / =8.8Hz, 2H), 7.45 (dd, / =4.4,2.8Hz, IH), 7.11 (dd, / =8.4,7.6Hz, IH), 6.82-6.72 (m, 2H), 4.78 (s, 2H) 3.76-3.73 (m, 2H), 3.66-3.61 (m, 2H), 2.70-2.63 (m, 2H), 2.43-2.40 (m, 2H). EXAMPLE 24
[0186] N-(2-aminophenyl)-4-(4-(4-(6-(2-methoxyethoxy)pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000092_0002
Example 24 (Compound a"10-11)
[0187] Similar procedure from Example 34 was followed to obtain the title compound using 2-methoxy-ethanol instead of 1-cyclopropyl-piperazine. MS found for C2QH30N4O4S as
(M+H)+ 531.08. 1H NMR (400MHz, dmso-d6): δ:9.58 (s, IH), 8.72 (d, / =2.0Hz, IH), 8.20 (dd,
/ =8.4,6.0Hz, IH), 7.98 (s, IH), 7.92 (d, / =8.4Hz, 2H), 7.57 (d, / =8.4Hz, 2H), 7.11 (d, / Attorney Docket No. 8493-000092/WO/POA
=7.2Hz, IH), 6.95-6.87 (m, 2H), 6.73 (d, / =7.6Hz, IH), 6.56 (t, / =7.2Hz, IH), 4.39-4.36 (m, 2H), 3.75-3.72 (m, 2H), 3.65-3.60 (m, 4H), 2.27 (s, 3H), 2.69-2.65 (m, 2H), 2.43-2.38 (m, 2H). EXAMPLE 25
[0188] N-(2-aminophenyl)-4-(4-(4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000093_0001
Example 25 (Compound a"10-15)
[0189] Similar procedure from Example 34 was followed to obtain the title compound using 1-methyl-piperazine instead of 1-cyclopropyl-piperazine. MS found for C31H34N6O2S as (M+H)+ 555.23. 1H NMR (400MHz, dmso-d6): δ:9.53 (s, IH), 8.66 (d, / =2.0Hz, IH), 7.89 (dd, / =8.4,7.2Hz, IH), 7.88 (d, / =8.0Hz, IH), 7.78 (s, IH), 7.53 (d, / =8.4Hz, 2H), 7.07 (t, / =8.0Hz, IH), 6.90-6.83 (m, 2H), 6.71 (d, / =8.0Hz, IH), 6.51 (t, / =7.6Hz, IH), 3.71-3.49 (m, 12H), 2.63-2.60 (m, 2H), 2.39-2.34 (m, 2H), 2.22 (s, 3H). EXAMPLE 26
[0190] N-(2-aminophenyl)-4-(4-(6,7-dihydropyrano[4,3-d]thiazol-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000093_0002
Example 26 (Compound a"0-63)
[0191] Tetrahydro-pyran-4-one (100 mg, 1.0 mmol), triethylamine (TEA) (0.139 mL, 1.0 eq), and trimethylchlorosilane (TMSCl) (0.127 mL, 1.0 eq) were mixed together in DMF and heated at 80 0C for 2 hours. After the reaction was done, the mixture was evaporated and re-dissolved in THF NaOAc (16.3 mg) and JV-bromosuccinimide (NBS) (177 mg, 1.0 eq) was added at -78 0C and stirred for 1 hour. When the reaction was done the mixture was extracted with EtOAc and the organic phase was dried and evaporated to give 3-bromo-tetrahydro-pyran-4-one that was Attorney Docket No. 8493-000092/WO/POA
used for next step without further purification. Following similar procedure for cyclization, hydrolysis and HATU coupling from Example 9 gave the title compound. MS found for C24H25N3O3S as (M+H)+ 436.23. 1H NMR (400MHz, dmso-d6): δ:9.53 (s, IH), 7.86 (d, / =8.4Hz, 2H), 7.47 (d, / =8.4Hz, 2H), 7.08 (d, / =7.2Hz, IH), 6.91-6.87 (m, IH), 6.69 (dd, / =8.0,6.8Hz, IH), 6.50 (t, / =6.4Hz, IH), 4.81 (s, 2H), 4.62 (s, 2H), 3.85-3.82 (m, 2H), 3.68-3.52 (m, 4H), 2.73-2.70 (m, 2H), 2.54-2.18 (m, 4H). EXAMPLE 27
[0192] 4-(4-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)tetrahydropyran-4-yl)-N- (2-aminophenyl)benzamide
Figure imgf000094_0001
-| Q Example 27 (Compound a"0-54)
[0193] 4-[4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid (40 mg, 0.116 mmol) in pyridine, catalytic amount of 4-dimethylaminopyridine (DMAP), and excess Ac2O were mixed together at room temperature. After the reaction was complete, the mixture was evaporated, washed with water, and extracted with EtOAc. The organic phase was
15 dried and evaporated to give 4-[4-(5-acetyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)- tetrahydro-pyran-4-yl] -benzoic acid. Similar HATU coupling procedure from Example 9 was followed to obtain the title compound. MS found for C26H28N4O3S as (M+H)+ 477.58. 1H NMR (400MHz, dmso-d6): δ:9.53 (s, IH), 7.89 (d, / =8.4Hz, 2H), 7.51 (t, / =8.4Hz, 2H), 7.10 (d, / =7.2Hz, IH), 6.92 (t, / =7.6Hz, IH), 6.72 (d, / =8.0Hz, IH), 6.54 (t, / =7.6Hz, IH), 4.84 (s,
20 2H), 4.61-4.57 (m, 2H), 3.69-3.57 (m, 6H), 2.80-2.29 (m, 6H), 2.05-1.98 (m, 3H). EXAMPLE 28
[0194] 4-(4-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)tetrahydropyran-4-yl)-N- (2-amino-5-(thiophen-2-yl)phenyl)benzamide Attorney Docket No. 8493-000092/WO/POA
Figure imgf000095_0001
Example 28 (Compound a"0-62)
[0195] Similar procedure from Example 27 was followed to obtain the title compound using (3-amino-4'-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester. MS found for C30H30N4O3S2 as (M+H)+ 559.56. 1H NMR (400MHz, dmso-d6): δ:9.63 (s, IH), 7.92 (d, / =8.2Hz, 2H), 7.52 (t, / =7.2Hz, 2H), 7.40 (s, IH), 7.31 (d, / =5.2Hz, IH), 7.25 (d, / =8.0Hz, IH), 7.19 (d, / =3.6Hz, IH), 7.00 (dd, / =5.2,1.6Hz, IH), 6.76 (d, / =8.4Hz, IH), 5.10 (s, 2H), 4.62-4.58 (m, 2H), 3.71- 3.55 (m, 6H), 2.85-2.69 (m, 2H), 2.57-2.33 (m, 4H), 2.06-2.00 (m, 3H). EXAMPLE 29
[0196] N-(2-aminophenyl)-4-(4-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000095_0002
Example 29 (Compound a"0-50)
[0197] A methanolic solution of 4-(4-thiocarbamoyl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (500 mg, 1.87 mmol) and 3-bromo-4-oxo-piperidine-l-carboxylic acid ethyl ester (l.Ogr, 2.0 eq) was added and heated in the microwave at 75 0C for 30 minutes. The reaction mixture was evaporated, washed with water, and extracted with EtOAc. The organic phase was dried and evaporated to be used for next step without further purification.
[0198] 2-[4-(4-methoxycarbonyl-phenyl)-tetrahydro-pyran-4-yl]-6,7-dihydro-4H- thiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester was dissolved in MeOH and 4N NaOH was added. The mixture was stirred at 50 0C for 24 hours. After hydrolysis was complete the solution was evaporated and suspended in water. Aqueous HCl was added slowly to permit the formation of precipitates that were filtered out. Attorney Docket No. 8493-000092/WO/POA
[0199] To 1 rnL of an aqueous solution of 4-[4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2- yl)-tetrahydro-pyran-4-yl] -benzoic acid (40 mg, 0.116 mmol) p-formaldehyde was added. The mixture was heated at 50 0C and stirred for 20 minutes. This mixture was cooled down at 0 0C and alpha-picoline-borane (15 mg, 1.2 eq) was added, followed by stirring overnight. The 5 mixture was evaporated and purified by reverse phase chromatography. HATU coupling was carried out following the procedure from Example 9 using benzene- 1,2-diamine, followed by reverse phase purification gave the title compound.. MS found for C25H28N4O2S as (M+H)+ 449.10. 1H NMR (400MHz, dmso-d6): δ:9.55 (s, IH), 7.89 (d, J=8.8Hz, 2H), 7.49 (d, / =8.4Hz, 2H), 7.10 (d, / =8.0Hz, IH), 6.91 (d, / =7.2Hz, IH), 6.72 (d, / =6.8Hz, IH), 6.54 (t, / 10 =7.2Hz, IH), 4.84 (s, 2H), 3.70-3.67 (m, 2H), 3.59-3.54 (m, 2H), 3.46 (s, 2H), 2.71-2.62 (m, 4H), 2.55-2.52 (m, 2H), 2.34-2.30 (m, 5H). EXAMPLE 30
[0200] N-(2-amino-5-fluorophenyl)-4-(4-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin- 2-yl)tetrahydropyran-4-yl)benzamide
Figure imgf000096_0001
-| 5 Example 30 (Compound a"0-59)
[0201] Similar procedure from Example 29 was followed to obtain the title compound using (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester De-protection was carried out with a mixture of DCM/TFA (1:1) at room temperature. MS found for C25H27FN4O2S as (M+H)+ 467.23. IH NMR (400MHz, dmso-dδ): δ:9.54 (s, IH), 7.84 (d, J =8.4Hz, 2H), 7.47 (d, 20 J =8.4Hz, 2H), 7.08 (dd, J =8.8,7.6Hz, IH), 6.75-6.67 (m, 2H), 4.77 (s, 2H), 3.67-3.64 (m, 2H), 3.56-3.53 (m, 2H), 2.67-2.60 (m, 6H), 2.52-2.29 (m, 4H), 2.27 (s, 3H). EXAMPLE 31
[0202] N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-(pyrrolidin-l-ylmethyl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide Attorney Docket No. 8493-000092/WO/POA
Figure imgf000097_0001
31 (Compound a"0-26)
[0203] Similar procedure from Example 32 was followed to obtain the title compound using pyrrolidine instead of 2-methoxy-ethanol. MS found for C30H32N4O2S2 as (M+H)+ 545.32. 1H NMR (400MHz, dmso-d6): δ: 9.64 (s, IH), 7.93 (d, / =8.4Hz, 2H), 7.51 (d, / =8.6Hz, 2H), 7.41 (s, IH) 7.35-7.31 (m, 2H), 7.26 (dd, / =8.2-5.4Hz, IH), 7.20 (d, / =3.2Hz, IH), 7.05-7.00 (m, IH), 6.77 (d, J=8.0Hz, IH), 5.11 (s, 2H), 3.76-3.70 (m, 2H), 3.63 (s, 2H), 3.61-3.52 (m, 2H), 2.62-2.53 (m, 2H), 2.41-2.31 (m, 2H), 1.69-1.61 (m, 4H). EXAMPLE 32
[0204] N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-((2-methoxyethoxy)methyl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000097_0002
32 (Compound a"0-28)
[0205] To a solution of 4-(4-thiocarbamoyl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (5.0gr, 17.92 mmol) in DMF was added acetic acid 3-chloro-2-oxo-propyl ester (6.32 mL, 3.0 eq) and DIPEA (6.24 mL, 2.0 eq). The reaction mixture was heated at 90 0C for 30 minutes in the microwave. Said mixture was then partitioned between ethyl acetate and water. The organic phase was dried with MgSO4 and evaporated under vacuum. The solid was used for next step without purification.
[0206] The solid 4-[4-(4-acetoxymethyl-4-hydroxy-4,5-dihydro-thiazol-2-yl)-tetrahydro- pyran-4-yl] -benzoic acid methyl ester was dissolved in MeOH and excess of p-TsOH was added and heated in the microwave for 20 minutes at 65 0C. The reaction mixture was washed with saturated of NaHCθ3 and extracted with EtOAc. The organic phase was dried with MgSO4 and evaporated under vacuum. Attorney Docket No. 8493-000092/WO/POA
[0207] Compound 4-[4-(4-hydroxymethyl-thiazol-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid methyl ester (2.0gr, 6.00 mmol) was dissolved in DCM and then MsCl (1.67 mL 3.5 eq) and TEA (1.80 mL, 2.0 eq) were added at 0 0C and stirred for 2 hours. When the reaction was complete, IN aqueous HCl was added to the reaction mixture. The organic phase was separated and dried over MgSO4 and evaporated under vacuum conditions to have the solid 4-[4-(4- methanesulfonyloxymethyl-thiazol-2-yl)-tetrahydro-pyran-4-yl] -benzoic acid methyl ester that was used for next step without further purification.
[0208] Compound 4-[4-(4-methanesulfonyloxymethyl-thiazol-2-yl)-tetrahydro-pyran-4-yl]- benzoic acid methyl ester (50 mg, 0.121 mmol) was dissolved in excess 2-methoxy-ethanol (1 mL), and potassium te/t-butoxide (13 mg, 1.0 eq) was added to the solution. The mixture was heated at 90 0C for 30 minutes in the microwave. The reaction mixture was evaporated extracted with EtOAc. The organic phase was dried over MgSO4 and evaporated to give a solid that was used for next step without further purification. Hydrolysis and HATU coupling was carried out following the same procedures from Example 64. MS found for C29H31N3O4S2 as (M+H)+ 550.09. 1H NMR (400MHz, dmso-d6): δ: 9.64 (s, IH), 7.93 (d, / =8.4Hz, 2H), 7.53 (d, / =8.4Hz, 2H), 7.48 (s, IH) 7.42 (s, IH), 7.31 (d, / =5.2Hz, IH), 7.25 (dd, / =8.0-6.2Hz, IH), 7.20 (d, / =3.2Hz, IH), 7.05-7.00 (m, IH), 6.73 (d, / =8.0Hz, IH), 5.12 (s, 2H) 3.73-3.68 (m, 2H), 3.61-3.51 (m, 6H), 3.46-3.40 (m, 2H), 2.21 (s, 3H) 2.62-2.53 (m, 2H), 2.42-2.32 (m, 2H). EXAMPLE 33 [0209] N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-(morpholinomethyl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000098_0001
a"0-30) [0210] Similar procedure from Example 32 was followed to obtain the title compound using morpholine instead of 2-methoxy-ethanol. MS found for C30H32N4O3S2 as (M+H)+ 561.20. 1H NMR (400MHz, dmso-d6): δ: 9.65 (s, IH), 7.92 (d, / =8.2Hz, 2H), 7.51 (d, / =8.4Hz, 2H), 7.41 (s, IH) 7.32 (d, / =5.4Hz, IH), 7.25 (dd, / =8.6,6.1Hz, IH), 7.19 (d, / =3.2Hz, IH), 7.01 (t, / Attorney Docket No. 8493-000092/WO/POA
=5.4Hz, IH), 6.78 (d, / =8.0Hz, IH), 5.1 (s, 2H), 3.74-3.70 (m, 2H), 3.61-3.52 (m, 6H), 2.65- 2.54 (m, 2H), 2.45-2.30 (m, 6H). EXAMPLE 34
[0211] N-(2-aminophenyl)-4-(4-(4-(6-(4-cyclopropylpiperazin-l-yl)pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000099_0001
Example 34 (Compound a"10-17)
[0212] 4-(4-thiocarbamoyl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (700 mg, 2.50 mmol), in MeOH was combined with 2-Bromo-l-(6-chloro-pyridin-3-yl)-ethanone (800 mg, 1.1 eq) and heated at 65°C for 2 hours. After reaction was complete, the reaction mixture was evaporated, diluted with EtOAc, and washed with a saturated aqueous NaHCO3 and brine. The organic phase was dried over MgSO4 and evaporated.
[0213] 4-{4-[4-(6-chloro-pyridin-3-yl)-thiazol-2-yl]-tetrahydro-pyran-4-yl}-benzoic acid methyl ester was dissolved in MeOH and IN NaOH was added. After the reaction was done, the reaction mixture was evaporated, suspended in water, and neutralized with IN HCl. The formed solids were collected by filtration. The solids were then suspended in acetonitrile and filtered to have a clean product 4-{4-[4-(6-chloro-pyridin-3-yl)-thiazol-2-yl]-tetrahydro-pyran-4-yl}- benzoic acid. Compound 4-{4-[4-(6-chloro-pyridin-3-yl)-thiazol-2-yl]-tetrahydro-pyran-4-yl}- benzoic acid (150 mg, 0.375 mmol) was dissolved in DMF. Then, 1-cyclopropyl-piperazine (82 mg, 1.1 eq), and DIPEA (0.2 mL, 3.2 eq) were added, and the reaction mixture was heated in the microwave at 90 0C for 30 minutes. After reaction was done, the reaction mixture was extracted with EtOAc. The organic phase was dried with MgSO4 and evaporated to have the solid material 4-(4-{4-[6-(4-cyclopropyl-piperazin-l-yl)-pyridin-3-yl]-thiazol-2-yl}-tetrahydro-pyran-4-yl)- benzoic acid.
[0214] 4-(4-{4-[6-(4-cyclopropyl-piperazin-l-yl)-pyridin-3-yl]-thiazol-2-yl}-tetrahydro- pyran-4-yl)-benzoic acid (60 mg, 0.122 mmol), benzene- 1,2-diamine (26 mg, 2.0 eq), HATU (56 Attorney Docket No. 8493-000092/WO/POA
mg, 1.2 eq), and DIPEA (0.042 rnL, 2.1 eq) were dissolved in DMF and stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was extracted with EtOAc and water. The organic phase was dried with MgSO4 and evaporated. The solid was purified by reverse phase chromatography to afford title compound. MS found for C33H36N6O2S as (M+H)+ 581.56. 1H NMR (400MHz, dmso-d6): δ:9.24 (s, IH), 8.35 (s, IH), 7.68 (d, /=6.2Hz, IH), 7.60 (d, / =8.2Hz, 2H), 7.51 (s, IH), 7.23 (d, / =8.4Hz, 2H), 6.79 (d, / =7.2Hz, IH), 6.62-6.51 (m, 2H), 6.41 (d, / =7.4Hz, IH), 6.22 (t, / =5.2Hz, IH), 4.51 (s, 2H), 3.45-3.38 (m, 2H), 3.32-3.25 (m, 2H), 3.18-3.11 (m, 4H), 2.38-2.22 (m, 6H), 2.15-2.05 (m, 2H), 1.31-1.23 (m, IH), 0.12-0.1 (m, 4H). EXAMPLE 35
[0215] N-(2-aminophenyl)-4-(4-(4-(6-(piperazin-l-yl)pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000100_0001
Example 35 (Compound a"10-13)
[0216] Similar procedure from Example 34 was followed to obtain the title compound using piperazine-1-carboxylic acid tert-butyl ester instead of 1-cyclopropyl-piperazine. An additional step was taken here. The amine was de-protected with a 1:1 mixture of TFA and DCM at room temperature and purified by reverse phase chromatography to have N-(2-amino-phenyl)-4-{4-[4- (6-piperazin-l-yl-pyridin-3-yl)-thiazol-2-yl]-tetrahydro-pyran-4-yl}-benzamide. MS found for C30H32N6O2S as (M+H)+ 541.16. 1H NMR (400MHz, dmso-d6): δ:9.54 (s, IH), 8.67 (d, / =2.0Hz, IH), 8.00 (dd, / =8.8,2.4Hz, IH), 7.88 (d, /=8.4Hz, 2H), 7.79 (s, IH), 7.53 (d, / =8.8Hz, 2H), 7.07 (d, / =8.0Hz, IH), 6.91-6.84 (m, 2H), 6.69 (d, / =6.8Hz, IH), 6.51 (t, / =8.4Hz, IH), 4.81 (s, 2H), 3.71-3.68 (m, 2H), 3.61-3.57 (m, 2H), 3.52-3.49 (m, 4H), 2.89-2.87 (m, 4H), 2.64- 2.60 (m, 2H), 2.42-2.34 (m, 2H). EXAMPLE 36
[0217] N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(thiazol-2-yl)tetrahydropyran-4- yl)benzamide Attorney Docket No. 8493-000092/WO/POA
Figure imgf000101_0001
36 (Comopund a"0-11 )
[0218] Similar procedure from Example 64 was followed to obtain the title compound using (3-amino-4'-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester instead of (2-amino-4-thiophen- 2-yl-phenyl)-carbamic acid tert-butyl ester. MS found for C27H24FN3O2S as (M+H)+ 474.32. 1H NMR (400MHz, dmso-d6): δ: 9.63 (s, IH), 7.92 (d, / =8.4Hz, 2H), 7.74 (d, / =3.2Hz, IH), 7.64 (d, / =7.2Hz, IH), 7.55-7.50 (m,6H), 7.45 (s, IH), 7.26 (dd, /=8.4,6.4Hz, IH), 7.15 (t, / =8.4Hz, 2H), 6.80 (d, / =8.4Hz, IH), 5.06 (s, 2H), 3.71-3.70 (m, 2H), 3.60-3.49 (m, 2H), 2.64-2.60 (m, 2H), 2.42-2.32 (m, 2H). EXAMPLE 37
[0219] N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-ethoxythiazol-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000101_0002
[0220] Compound A (0.49g, 1.8 mmol) and ethyl chloroacetate (1.11 mL, 10.4 mmol) were dissolved in EtOH (15 mL). The resulting mixture was heated at 60 0C overnight, concentrated, and purified by silica gel chromatography (1% MeOH/DCM) to afford Compound B (0.35g, 58%). MS m/z: 348 (MH+). Compound B (0.35g, 1.0 mmol) was hydrolyzed with 2N aqueous NaOH (5 mL) and THF (2 mL) to afford corresponding acid Compound C (0.30g, 90%). MS m/z: 334 (MH+). Compound C (0.2Og, 0.6 mmol) was coupled with amine Compound D (0.18g, 0.6 mmol) in the presence of HATU (0.46g, 1.2 mmol) and triethylamine (0.25 mL, 1.8 mmol) in Attorney Docket No. 8493-000092/WO/POA
DMF (10 rnL) to afford crude amide Compound E. MS m/z: 606 (MH+). Crude Compound E was treated with 4N HCl/dioxane, concentrated and purified by preparative HPLC to afford Example 37 (0.041g, 13% for two steps). MS (C27H27N3O3S2) m/z: 506 (MH+). NMR 1U NMR (dmso-d6): δ 9.66 (s, IH), 7.94 (d, /=8.4 Hz, 2H), 7.52(d, /=8.4 Hz, 2H), 7.42 (s, IH), 7.31 (d, /= 5.2 Hz, IH), 7.25 (d, /=8.4 Hz, IH), 7.18 (d, /=2.4 Hz, IH), 7.02 (t, /=3.2 Hz, IH), 6.87 (d, /=8.4 Hz, IH), 6.41 (s, IH), 5.12 (s, 2H), 4.01 (q, /=7.2 Hz, 2H), 3.68 (m, 2H), 3.58 (m, 2H), 2.53 (m, 2H), 2.31 (m, 2H), 1.28 (t, /=7.2 Hz, 3H). EXAMPLE 38
[0221] 4-(4-(lH-tetrazol-5-yl)tetrahydropyran-4-yl)-N-(2-amino-5-(thiophen-2- yl)phenyl)benzamide
Figure imgf000102_0001
Example 38 (Compound g-03)
[0222] A solution of 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (400 mg, 1.63 mmol), trimethylsilyl azide (TMSN3) (40 mg, 2.1 eq), and Bu2Sn(O) (40 mg, 1.0 eq) in DME was heated in the microwave at 150 0C for 4 hours. After the reaction was done the mixture was washed with water and extracted with EtOAc. The organic phase was dried and evaporated to give 4-[4-(lΗ-tetrazol-5-yl)-tetrahydro-pyran-4-yl]-benzoic acid methyl ester.
[0223] Hydrolysis HATU coupling and amine de-protection were carried out following the same procedures from Example 64. MS found for C23H22N6O2S as (M+H)+ 447.56. 1H NMR (400MHz, dmso-dβ): δ:9.64 (s, IH), 7.92 (d, / =8.4Hz, 2H), 7.42-7.35 (m, 3H), 7.28 (d, / =5.4Hz, IH), 7.22 (dd, / =4.0,3.6Hz, IH), 7.15 (t, / =6.0Hz, IH), 6.95 (dd, / =8.4,6.4Hz, IH), 6.73 (d, / =6.4Hz, IH), 5.08 (s, 2H), 3.83-3.73 (m, 2H), 3.33-3.25 (m, 2H), 2.66-2.60 (m, 2H), 2.32-2.22 (m, 2H), 1.4 (s, IH). EXAMPLE 39
[0224] 4-(4-(lH-tetrazol-5-yl)tetrahydropyran-4-yl)-N-(4-amino-4'-fluorobiphenyl-3- yl)benzamide Attorney Docket No. 8493-000092/WO/POA
Figure imgf000103_0001
Example 39 (Compound g-02)
[0225] Similar procedure from Example 38 was followed to obtain the title compound using (3-amino-4'-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester instead of (2-amino-4-thiophen- 2-yl-phenyl)-carbamic acid tert-butyl ester. MS found for C25H23FN6O2 as (M+H)+ 459.41. 1H NMR (400MHz, dmso-d6): δ:9.65 (s, IH), 8.93 (d, / =8.4Hz, 2H), 7.55-7.50 (m, 2H), 7.45-7.35 (m, 3H), 7.25 (d, / =7.2Hz, IH), 7.15 (t, / =8.0Hz, 2H), 6.81 (d, / =8.4Hz, IH), 5.05 (s, 2H), 3.85-3.78 (m, 2H), 3.35-3.28 (m, 2H), 2.70-2.62 (m, 2H), 2.33-2.28 (m, 2H), 2.42 (s, IH). EXAMPLE 40
[0226] N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(4-ethoxythiazol-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000103_0002
[0227] Compound C (O.lOg, 0.3 mmol) was coupled with amine Compound F (0.092g, 0.3 mmol) in the presence of HATU (0.23g, 0.6 mmol), and triethylamine (0.15 mL, 1.1 mmol) in DMF (5 mL) to afford crude amide Compound G. MS m/z: 618 (MH+). Crude Compound G was treated with 4N HCl /dioxane, concentrated and purified by preparative HPLC to afford Example 40. (0.021g, 14% for two steps). MS (C29H28FN3O3S) m/z: 518 (MH+). NMR 1H NMR (dmso-d6): δ 9.67 (s, IH), 7.93 (d, /=8.4 Hz, 2H), 7.52(m, 4H), 7.43 (s, IH), 7.25 (d, /=8.0 Hz, IH), 7.17 (t, /=8.8 Hz, 2H), 6.82 (d, /=8.4 Hz, IH), 6.41 (s, IH), 5.18 (s, 2H), 4.00 (q, /=7.2 Hz, 2H), 3.68 (m, 2H), 3.55 (m, 2H), 2.50 (m, 2H), 2.32 (m, 2H), 1.28 (t, /=7.2 Hz, 3H). Attorney Docket No. 8493-000092/WO/POA
EXAMPLE 41
[0228] N-(2-aminophenyl)-4-(4-(4-(pyrazin-2-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000104_0001
Example 41 (Compound a"12-01 )
[0229] Similar procedure from Example 9 was followed to obtain the title compound using 2-bromo-l-(pyrazin-2-yl)ethanone. MS found for C25H23N5O2S as (M+H)+ 458.25. 1U NMR (400MHz, dmso-d6): δ:9.59 (s, IH), 9.29 (s, IH), 8.64 (s, IH), 8.59 (s, IH), 8.32 (s, IH), 7.93 (d, / =8.0Hz, 2H), 7.60 (d, / =8.2Hz, 2H), 7.11 (d, / =7.6Hz, IH), 6.92 (t, / =6.8Hz, IH), 6.73 (d, / =7.6Hz, 2H), 6.54 (t, /=7.2Hz, IH), 4.85 (s, 2H), 3.74-3.62 (m, 4H), 2.72-2.50 (m, 4H). EXAMPLE 42
[0230] W-hydroxy-4-(4-(4-(pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide
Figure imgf000104_0002
Example 42 (Compound a"10-01)
[0231] Similar procedure from Example 22 was followed to obtain the title compound using O-(l,l,2,2-tetramethyl-propyl)-hydroxylamine. De-protection of TBS group was done by heating the protected hydroxylamine with IN HCl for 30 minutes.. MS found for C2OHIgN3O3S as (M+H)+ 382.65. 1U NMR (400MHz, dmso-d6): δ:11.14 (s, IH), 9.14 (d, / =1.6Hz, IH), 8.99 (s, IH), 8.51 (dd, / =4.8-3.2Hz, IH), 8.28-8.19 (m, IH), 7.69 (d, / =8.4Hz, 2H), 7.52 (d, / =8.4Hz, 2H), 7.46-7.43 (m, IH), 3.75-3.73 (m, 2H), 3.62-3.58 (m, 2H), 2.67-2.64 (m, 2H), 2.40- 2.33 (m, 2H). EXAMPLE 43
[0232] JV-hydroxy-4-(4-(thiazol-2-yl)tetrahydropyran-4-yl)benzamide Attorney Docket No. 8493-000092/WO/POA
Figure imgf000105_0001
43 (Compound a"0-09)
[0233] Similar procedure from Example 64 was followed to obtain the title compound using 0-(l,l,2,2-tetramethyl-propyl)-hydroxylamine instead of (2-amino-4-thiophen-2-yl-phenyl)- carbamic acid tert-butyl ester. De-protection of TBS group was done by heating the protected hydroxylamine with IN HCl for 30 minutes. MS found for Ci5Hi6N2O3S as (M+H)+ 305.12. 1H NMR (400MHz, dmso-d6): δ:11.08 (s, IH), 8.94 (s, IH), 7.68 (d, / =3.2Hz, IH), 7.63 (d, / =8.8Hz, 2H), 7.60 (d, / =3.2Hz, IH), 7.39 (d, / =8.4Hz, 2H), 3.69-3.64 (m, 2H), 3.50-3.45 (m, 2H), 2.56-2.52 (m, 2H), 2.32-2.25 (m, 2H). EXAMPLE 44
[0234] W-hydroxy-4-(4-(4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000105_0002
Example 44 (Compound a"10-14)
[0235] 4-(4-{4-[6-(4-methyl-piperazin-l-yl)-pyridin-3-yl]-thiazol-2-yl}-tetrahydro-pyran-4- yl)-benzoic acid (200 mg, 0.215 mmol), HATU (90 mg, 1.1 eq), H2N-OTBS (2.0 eq), and TEA (0.1 mL, 3 eq) were mixed in DMF and stirred for 2 hours. The reaction mixture was washed with water and then extracted with EtOAc. The organic phase was evaporated, suspended in IN HCl, and slowly evaporated at 50 0C for 30 minutes to give title compound. MS found for C25H29N5O3S as (M+H)+ 480.15. 1H NMR (400MHz, dmso-d6): δ:11.13 (s, IH), 8.99 (s, IH), 8.68 (d, / =2.4Hz, IH), 8.00 (dd, / =8.8,6.4Hz, IH), 7.81 (s, IH), 7.68 (d, / =8.4Hz, 2H), 7.50 (d, J =SAUz, 2H), 6.87 (d, / =8.8Hz, IH), 3.73-3.70 (m, 2H), 3.61-3.56 (m, 2H), 3.53-3.50 (m, 4H), 2.65-2.60 (m, 2H), 2.44-2.20 (m, 4H), 2.38-2.32 (m, 2H), 2.22 (s, 3H). Attorney Docket No. 8493-000092/WO/POA
EXAMPLE 45
[0236] N-(2-amino-5-(5-chlorothiophen-2-yl)phenyl)-4-(4-(thiazol-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000106_0001
45 (Compound a"0-14)
[0237] Similar procedure from Example 64 was followed to obtain the title compound using [2-amino-4-(5-chloro-thiophen-2-yl)-phenyl]-carbamic acid tert-butyl ester instead of (2-amino- 4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester. MS found for C27H24FN3O2S as (M+H)+ 474.22. 1H NMR (400MHz, dmso-d6): δ:9.64 (s, IH), 7.92 (d, / =8.4Hz, 2H), 7.73 (d, / =3.2Hz, IH), 7.65 (d, /=3.2Hz, IH), 7.51 (d, / =8.4Hz, 2H), 7.35 (s, IH), 7.20 (dd, / =8.4,6.4Hz, IH), 7.06 (d, / =4.0Hz, IH), 7.01 (d, / =4.1Hz, IH), 6.75 (d, / =8.4Hz, IH), 5.21 (s, 2H), 3.73- 3.70 (m, 2H), 3.57-3.52 (m, 2H), 2.63-2.59 (m, 2H), 2.40-2.35 (m, 2H). EXAMPLE 46
[0238] N-(2-amino-5-(5-methylthiophen-2-yl)phenyl)-4-(4-(thiazol-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000106_0002
Example 46 (Compound a"0-13)
[0239] Similar procedure from Example 64 was followed to obtain the title compound using [2-amino-4-(5-methyl-thiophen-2-yl)-phenyl]-carbamic acid tert-butyl ester instead of (2-amino- 4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester. MS found for C26H25N3O2S2 as (M+H)+ 476.07. 1H NMR (400MHz, dmso-d6): δ: 9.61 (s, IH), 7.92 (d, / =8.4Hz, 2H), 7.72 (d, / =3.4Hz, IH), 7.61 (d, / =3.4Hz, IH), 7.51 (d, / =8.4Hz, 2H),, 7.32 (s, IH), 7.18 (d, / =5.4Hz, IH), 6.95 (d, / =4.2Hz, IH), 6.72 (d, /=8.2Hz, IH), 6.68 (s, IH), 5.06 (s, 2H) 3.74-3.68 (m, 2H), 3.58-3.50 (m, 2H), 2.66-2.56 (m, 2H), 2.38 (s, 3H) 2.42-2.33 (m, 2H). Attorney Docket No. 8493-000092/WO/POA
EXAMPLE 47
[0240] N-(2-aminophenyl)-4-(4-(4-(4-(4-methylpiperazin-l-yl)phenyl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000107_0001
Example 47 (Compound a"0-34)
[0241] Compound H (0.62g, 2.2 mmol), and Compound I (0.65g, 2.3 mmol) were dissolved in MeOH (10 mL). The resulting mixture was stirred overnight, concentrated, and purified by preparative HPLC to afford Compound J (0.54g, 54%). MS m/z: 458, 460 (MH+). A solution of tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, 0.054g, 0.059 mmol) and 2,2'- bis(diphenylphosphino)-l,r-binaphthyl (BINAP, 0.1 Ig, 0.18 mmol) in dioxane (10 mL) under nitrogen atmosphere was stirred for 10 minutes before the addition of Compound J (0.54g, 1.2 mmol) and JV-methylpiperazine (0.27 mL, 2.4 mmol). After the sample was stirred for 10 minutes, the resultant solution was treated with KO1Bu (0.2Og, 1.8 mmol). The mixture was stirred and heated at 80 0C overnight, then cooled down, and treated with EtOAc and filtered. The solution was washed with brine, dried, concentrated and purified by preparative HPLC to afford Compound K (0.18g, 31%). MS m/z: 478 (MH+). Compound K (0.18g, 0.4 mmol) was hydrolyzed with 2N aqueous NaOH (5 mL) and THF (2 mL). It was then coupled with phenylenediamine (0.062g, 0.6 mmol) in the presence of HATU (0.28g, 0.7 mmol) and TEA (0.16 mL, 1.1 mmol) in DMF (5 mL). The resultant mixture was purified by preparative HPLC to afford title compound (0.018g, 9%). MS (C32H35N5O2S) m/z: 555 (MH+). 1U NMR (dmso- d6): δ 9.57 (s, IH), 7.90 (d, /=8.4 Hz, 2H), 7.78 (d, /=8.8 Hz, 2H), 7.75 (s, IH), 7.55 (d, /=8.4 Hz, 2H), 7.11 (d, /=6.8 Hz, IH), 6.95 (d, /=8.8 Hz, 2H), 6.91 (t, /=7.2 Hz, IH), 6.72 (d, /=8.0 Attorney Docket No. 8493-000092/WO/POA
Hz, IH), 6.54 (t, /=8.4 Hz, IH), 4.85 (s, 2H), 3.74 (m, 2H), 3.64 (m, 2H), 3.28 (m, 4H), 3.17 (m, 4H), 2.65 (m, 2H), 2.40 (m, 2H), 2.23 (s, 3H). EXAMPLE 48
[0242] N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(l-(thiazol-2-yl)cyclopropyl)benzamide
Figure imgf000108_0001
Example 48 (Compound aO-79)
[0243] Similar procedure from Example 64 was followed to obtain the title compound using 4-(l-cyano-cyclopropyl)-benzoic acid methyl ester instead of 4-(4-cyano-tetrahydro-pyran-4-yl)- benzoic acid methyl ester. MS found for C25H20FN3OS as (M+H)+ 430.21. 1H NMR (400MHz, dmso-dβ): δ:9.73 (s, IH), 7.99 (d, / =8.4Hz, 2H), 7.64 (d, / =3.2Hz, IH), 7.57-7.52 (m, 4H), 7.47-7 '.44 (m, 2H), 7.26 (dd, / =8.0-6.0Hz, IH), 7.18 (t, / =8.8Hz, 2H), 6.83 (d, / =8.4Hz, IH), 5.08 (s,2H), 1.65-1.62 (m, 2H), 1.46-1.43 (m, 2H). EXAMPLE 49
[0244] N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(2,3-dihydropyridin-2-yl)tetrahydropyran- 4-yl)benzamide
Figure imgf000108_0002
Example 49 (Compound f-03)
[0245] To 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (200 mg, 0.81 mmol) in toluene was added ethynyl-trimethyl-silane (800 mg, 10 eq) and CpCo(CO)2 (0.2eq). The mixture was irradiated with light of 400nm under stirring conditions for 2 days. Toluene was removed by evaporation. The solids were washed with water and the compound was extracted with EtOAc. The organic phase was dried and evaporated. 4-[4-(4,6-bis-trimethylsilanyl- pyridin-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid methyl ester was dissolved in THF and TBAF Attorney Docket No. 8493-000092/WO/POA
was added in excess. The reaction mixture was stirred overnight at room temperature. After the reaction was done, it was extracted with EtOAc. The organic phase was evaporated to be used for next step. Hydrolysis, HATU coupling, and amine de-protection were carried out following the same procedures from Example 64 using (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester instead of (3-amino-4'-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester. MS found for C27H25N3O2S as (M+H)+ 456.26. 1H NMR (400MHz, dmso-d6): δ:9.59 (s, IH), 8.51 (t, / =4.8Hz, IH), 7.87 (d, / =8.4Hz, 2H), 7.70-7.66 (m, IH), 7.47 (d, / =8.8Hz, 2H), 7.39 (d, / =8.8Hz, 2H), 7.30 (t, / =4.0Hz, IH), 7.24 (dd, / =8.4,6.0Hz, IH), 7.18-7.14 (m, 2H), 7.01-6.99 (m, IH), 6.75 (d, J=8.4Hz, IH), 5.09 (s, 2H), 3.64-3.67 (m, 2H), 3.58-3.46 (m, 2H), 2.72-2.69 (m, 2H), 2.34-2.29 (m, 2H). EXAMPLE 50
[0246] N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(l-(thiazol-2-yl)cyclopropyl)benzamide
Figure imgf000109_0001
Example 50 (Compound aO-80)
[0247] Similar procedure from Example 64 was followed to obtain the title compound using 4-(l-cyano-cyclopropyl)-benzoic acid methyl ester instead of 4-(4-cyano-tetrahydro-pyran-4-yl)- benzoic acid methyl ester. MS found for C23Hi9N3OS2 as (M+H)+ 418.20. 1H NMR (400MHz, dmso-dβ): δ:9.73 (s, IH), 7.99 (d, / =8.4Hz, 2H), 7.64 (d, / =3.2Hz, IH), 7.56 (d, / =8.4Hz, 2H), 7.45-7.35 (m, 2H), 7.22 (dd, / =5.2,4.4Hz, IH), 7.21 (d, / =2.8Hz, IH), 6.78 (d, / =8.4Hz, IH), 5.13 (s, 2H), 1.65-1.62 (m, 2H), 1.46-1.43 (m, 2H). EXAMPLE 51
[0248] N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(5-(pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide Attorney Docket No. 8493-000092/WO/POA
Figure imgf000110_0001
Example 51 (Compound a"0-40)
[0249] To the mixture of methyl 4-(4-(thiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate (570 mg, 1.88 mmol) in DMF (5 mL) was added a IM solution of bromine in DMF (1.9 mL, 1.88 mmol). After 2 hours, additional IM solution of bromine in DMF (1.9 mL, 1.88 mmol) was added. The reaction mixture was then concentrated to half its volume and poured into water (25 mL). The resulting solid was filtered and washed with water and dried to give methyl 4-(4-(5- bromothiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate. 1H NMR (400MHz, dmso-d6): δ 7.99 (d, / = 8.0 Hz, 2H); 7.58 (s, IH); 7.41 (d, / = 8.0 Hz, 2H); 3.87 (s, 3 H); 3.91-3.84 (m, 2H); 3.73- 3.68 (m, 2H); 2.63-2.59 (m, 2H); 2.41-2.37 (m, 2H); MS found for Ci6Hi6BrNO3S (m/z): 3840.3 [MM].
[0250] A mixture pyridin-3-ylboronic acid (128 mg, 1.05 mmol), methyl 4-(4-(5- bromothiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate (200 mg, 0.52 mmol), potassium carbonate (144 mg, 1.05 mmol), and PdCi2(dppf) (76 mg, 0.11 mmol) in toluene/ethanol/water (2 mL/1 mL/1 mL) was heated in microwave (Emry's Optimizer) at 100 0C for 20 minutes. The reaction mixture was then poured into EtOAc/hexanes mixture and the resultant solid was filtered and dried. The dried solid was used for next step without purification. MS found for C2IH20N2O3S (m/z): 381.20 [M++l]. To the above crude ester in methanol (5 mL) and THF (2 mL), NaOH (1.0 M, 5.0 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was then diluted with water and acidified with IN HCl to about pH 7. The aqueous solution was then concentrated and diluted with methanol. The solids were filtered. The filtrate was then concentrated and used for next step. MS found for C20H18N2O3S (m/z): 367.39 [MM]. To the above crude carboxylic acid in NMP (3 mL), was added HATU (300 mg, 0.76 mmol), tert-buty\ 2-amino-4-(thiophen-2-yl)phenylcarbamate (303 mg, 1.05 mmol) and N- methylmorpholine (NMM) (0.3 mL, 2.62 mmol) and stirred at 50 0C for 16 hours. The reaction mixture was then diluted with water and acetonitrile/methanol and the resulting solid was filtered and washed with water and dried to give te/t-butyl 2-(4-(4-(5-(pyridin-3-yl)thiazol-2-yl)- Attorney Docket No. 8493-000092/WO/POA
tetrahydro-2H-pyran-4-yl)benzamido)-4-(thiophen-2-yl)phenylcarbamate. MS found for C35H34N4O4S2 as (M+H)+ 639.17. To the above butoxycarbonyl (Boc) protected compound was added 4.0 M HCl dioxane (6.0 rnL) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated and diluted with water and acetonitrile and directly purified by preparative HPLC followed by lyophilization to give the title compound. MS found for C30H26N4O2S2 as (M+H)+ 538.91. 1H NMR (400MHz, dmso-d6): δ 9.68 (s, IH); 8.82 (s, IH); 8.50 (d, / = 3.6 Hz, IH); 8.25 (s, IH); 7.99-7.95 (m, 3H); 7.59 (d, / = 8.8 Hz, 2H) 7.41-7.39 (m, 2H); 7.32-7.19 (m, 4H); 7.02-7.00 (m, IH); 6.77 (d, / = 8.4 Hz, IH); 5.12 (brs, 2H); 3.76-3.73 (m, 2H); 3.65-3.60 (m, 2H); 2.66-2.63 (m, 2H) ; 2.41-2.39 (m, 2H). EXAMPLE 52
[0251] N-(2-amino-5-(5-methylthiophen-2-yl)phenyl)-4-(l-(thiazol-2- yl)cyclopropyl)benzamide
Figure imgf000111_0001
Example 52 (Compound aO-81 )
[0252] Similar procedure from Example 64 was followed to obtain the title compound using 4-(l-cyano-cyclopropyl)-benzoic acid methyl ester instead of 4-(4-cyano-tetrahydro-pyran-4-yl)- benzoic acid methyl ester. MS found for C24H2IN3OS2 as (M+H)+ 432.23. 1H NMR (400MHz, dmso-d6): δ:9.71 (s, IH), 7.98 (d, / =8.0Hz, 2H), 7.64 (d, / =3.6Hz, IH), 7.56 (d, / =8.4Hz, 2H), 7.45 (d, / =2.8Hz, IH), 7.36 (s, IH), 7.18 (dd, / =8.4,6.4Hz, IH), 6.98 (d, / =3.6Hz, IH), 6.75 (d, / =8.4Hz, IH), 6.69-6.68 (m, IH), 5.08 (s,2H), 2.39 (s, 3H), 1.64-1.62 (m, 2H), 1.46-1.44 (m, 2H).
EXAMPLE 53
[0253] N-hydroxy-4-(4-(4-(pyrazin-2-yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide
Figure imgf000111_0002
Example 53 (Compound a"12-02) Attorney Docket No. 8493-000092/WO/POA
[0254] Similar procedure from Example 22 was followed to obtain the title compound using 2-bromo-l-(pyrazin-2-yl)ethanone. MS found for Ci9Hi8N4O3S as (M+H)+ 383.85. 1U NMR (400MHz, dmso-dβ): δ:11.09 (s, IH), 9.24 (d, / =1.2Hz, IH), 8.61-8.55 (m, 2H), 8.28 (s, IH), 7.66 (d, / =8.4Hz, 2H), 7.50 (d, / =8.4Hz, 2H), 3.72-3.70(m, 2H), 3.60-3.55 (m, 2H), 2.66-2.62 (m, 2H), 2.38-2.33 (m, 2H). EXAMPLE 54
[0255] N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(4-(pyrazin-2-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000112_0001
Example 54 (Compound a"12-03)
[0256] Similar procedure from Example 22 was followed to obtain the title compound using l-pyrazin-2-yl-ethanone. MS found for C3IH26FN5O2SaS (M+H)+ 552.22. 1H NMR (400MHz, dmso-dβ): δ:9.65 (s, IH), 9.29 (d, / =1.2Hz, IH), 8.65 (t, / =2.8Hz, IH), 8.60 (d, / =2.4Hz, IH), 8.33 (s, IH), 7.95 (d, / =8.4Hz, 2H), 7.62 (d, / =8.8Hz, 2H), 7.54-7.50 (m, 2H), 7.44 (s, IH), 7.25 (dd, / =8.4,5.6Hz, IH), 7.17 (t, / =9.2Hz, 2H), 6.80 (d, / =8.4Hz, IH), 5.05 (s, 2H), 3.77- 3.74 (m, 2H), 3.68-3.63 (m, 2H), 2.73-2.63 (m, 2H), 2.47-2.46 (m, 2H). EXAMPLE 55
[0257] N-(2-aminophenyl)-4-(l-(4-(pyrazin-2-yl)thiazol-2-yl)cyclopropyl)benzamide
Figure imgf000112_0002
Example 55 (Compound a12-01 )
[0258] Similar procedure from Example 22 was followed to obtain the title compound using 4-(l-cyano-cyclopropyl)-benzoic acid methyl ester instead of 4-(4-cyano-tetrahydro-pyran-4-yl)- benzoic acid methyl ester. MS found for C23Hi9N5OS as (M+H)+ 414.65. 1U NMR (400MHz, dmso-d6): δ:9.76 (s, IH), 9.19 (d, / =1.6Hz, IH), 8.64 (t, / =4.4Hz, IH), 8.58 (d, / =2.8Hz, IH), Attorney Docket No. 8493-000092/WO/POA
8.15 (s, IH), 8.00 (d, / =8.0Hz, 2H), 7.63 (d, / =8.0Hz, 2H), 7.18 (d, / =7.2Hz, IH), 6.99 (t, / =7.6Hz, IH), 6.82 (d, / =7.2Hz, IH), 6.68-6.66 (m, IH), 1.82-1.79 (m, 2H), 1.54-1.51 (m, 2H). EXAMPLE 56
[0259] N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(l-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridine-2-yl)cyclopropyl)benzamide
Figure imgf000113_0001
Example 56 (Compound a0-117)
[0260] Similar procedure from Example 29 was followed to obtain the title compound using 4-(l-cyano-cyclopropyl)-benzoic acid methyl ester instead of 4-(4-cyano-tetrahydro-pyran-4-yl)- benzoic acid methyl ester. MS found for C29H27FN4OS as (M+H)+ 499.19. 1H NMR (400MHz, dmso-dβ): δ:9.71 (s, IH), 7.97 (d, / =8.0Hz, 2H), 7.56-7.52 (m, 4H), 7.46 (s, IH), 7.27 (dd, / =8.4-6.4Hz, IH), 7.18 (t, / =8.8Hz, 2H), 6.83 (d, / =8.4Hz, IH), 5.07 (s, 2H), 3.41 (s, 2H), 2.64- 2.61 (m, 4H), 2.29 (s, 3H), 1.59-1.57 (m, 2H), 1.41-1.38 (m, 2H). EXAMPLE 57
[0261] N-(2-amino-5-fluorophenyl)-4-(4-(4-(pyrazin-2-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000113_0002
Example 57 (Compound a"12-04)
[0262] Similar procedure from Example 22 was followed to obtain the title compound using (2-amino-4-fluoro-phenyl)-carbamic acid tert-butyl ester MS found for C2SH22FNsO2S as (M+H)+ 476.41. 1U NMR (400MHz, dmso-d6): δ:9.58 (s, IH), 9.29 (d, / =1.2Hz, IH), 8.65 (t, / =2.4Hz, IH), 8.60 (d, / =2.4Hz, IH), 8.33 (s, IH), 7.91 (d, / =8.4Hz, 2H), 7.61 (d, / =8.4Hz, 2H), 7.11 (dd, / =8.4,7.6Hz, IH), 4.79 (s, 2H) 3.77-3.74 (m, 2H), 3.67-3.62 (m, 2H), 2.72-2.69 (m, 2H), 2.47-2.41 (m, 2H). Attorney Docket No. 8493-000092/WO/POA
EXAMPLE 58
[0263] N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(l-(6,7-dihydropyrano[4,3-d]thiazol-2- yl)cyclopropyl)benzamide
Figure imgf000114_0001
Example 58 (Compound aO-122)
[0264] Similar procedure from Example 26 was followed to obtain the title compound using 4-(l-cyano-cyclopropyl)-benzoic acid methyl ester and (3-amino-4'-fluoro-biphenyl-4-yl)- carbamic acid tert-butyl ester. MS found for C28H24FN3O2S as (M+H)+ 486.54. 1H NMR (400MHz, dmso-dβ): δ:9.71 (s, IH), 7.97 (d, / =8.4Hz, 2H), 1.55-1 Al (m, 5H), 7.28-7.25 (m, IH), 7.18 (t, / =8.8Hz, 2H), 6.82 (d, / =8.0Hz, IH), 5.07 (s, 2H), 4.61 (s, 2H), 3.85 (t J=5.6Hz, 2H), 2.69 (t, / =5.6Hz, 2H), 1.61-1.58 (m, 2H), 1.43-1.42 (m, 2H). EXAMPLE 59
[0265] N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(pyridin-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000114_0002
Example 59 (Compound e-05)
[0266] Similar procedure from Example 49 was followed to obtain the title compound using (3-amino-4'-fluoro-biphenyl-4-yl)-carbamic acid tert-buty\ ester. MS found for C2QH26FN3O2 as (M+H)+ 468.20. 1U NMR (400MHz, dmso-d6): δ:9.59 (s, IH), 8.52 (dd, / =4.8,3.6Hz, IH), 7.87 (d, / =8.8Hz, 2H), 7.71-7.66 (m, IH), 7.53-7.38 (m, 6H), 7.24 (dd, / =8.4,6.0Hz, IH), 7.19-7.14 (m, 3H), 6.80 (d, / =8.0Hz, IH), 5.03 (s, 2H), 3.68-3.64 (m, 2H), 3.51-3.46 (m, 2H), 2.72-2.68 (m, 2H), 2.34-2.24 (m, 2H). Attorney Docket No. 8493-000092/WO/POA
EXAMPLE 60
[0267] N-(2-amino-5-(5-chlorothiophen-2-yl)phenyl)-4-(4-(pyridin-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000115_0001
Example 60 (Compound e-06)
[0268] Similar procedure from Example 49 was followed to obtain the title compound using [2-amino-4-(5-chloro-thiophen-2-yl)-phenyl]-carbamic acid tert-butyl ester instead of (2-amino- 4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester. MS found for C27H24CIN3O2S as (M+H)+ 490.63. 1H NMR (400MHz, dmso-d6): δ:9.58 (s, IH), 8.52 (d, / =4.0Hz, IH), 7.86 (d, /=8.8Hz, 2H), 7.71-7.66 (m, IH), 7.46 (d, / =8.8Hz, 2H), 7.39-7.34 (m, 2H), 7.20-7.14 (m, 2H), 7.06-7.00 (m, 2H), 6.75 (d, / =8.4Hz, IH), 5.18 (s, 2H), 3.67-3.64 (m, 2H), 3.51-3.46 (m, 2H), 2.72-2.63 (m, 2H), 2.34-2.22 (m, 2H). EXAMPLE 61
[0269] N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(5-(l-hydroxyethyl)-4-methylthiazol-2- yl)tetrahydropyran-4-yl)benzamide
Figure imgf000115_0002
61 (Compound a"0-20)
[0270] To a solution of 4-[4-(5-Acetyl-4-methyl-thiazol-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid (100 mg, 0.289 mmol) in MeOH was added NaBH4 (22 mg, 2 eq) at 0 0C and stirred for 1 hour. After reaction was done, it was quenched with aqueous HCl and stirred for 1 more hour. Reaction mixture was evaporated and purified by reverse phase chromatography to have pure 4- {4-[5-(l-hydroxy-ethyl)-4-methyl-thiazol-2-yl]-tetrahydro-pyran-4-yl} -benzoic acid. HATU coupling and amine de-protection was carried out following the procedure from Example 64 to Attorney Docket No. 8493-000092/WO/POA
afford title compound. MS found for C30H30FN3O3S as (M+H)+ 532.25. 1U NMR (400MHz, dmso-d6): δ:9.64 (s, IH), 7.92 (d, / =8.4Hz, 2H), 7.54-7.51 (m, 4H), 7.45 (d, / =1.2Hz, IH), 7.25 (dd, / =8.4,6.4Hz, IH), 7.17 (t, / =8.2Hz, 2H), 6.81 (d, / =8.4Hz, IH), 5.44 (d, / =3.6Hz, IH), 5.06 (s, 2H), 4.91-4.89 (m, IH), 3.69-3.66 (m, 2H), 3.59-3.54 (m, 2H), 2.57-2.54 (m, 2H), 2.35- 2.29 (m, 2H), 2.23 (s, 3H), 1.26 (d, J=6.4Hz, 3H). EXAMPLE 62
[0271] N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(4,5-dimethylthiazol-2-yl)tetrahydropyran- 4-yl)benzamide
Figure imgf000116_0001
62 (Compound a"0-22) [0272] Similar procedure from Example 9 was followed to obtain the title compound using
3-chloro-butan-2-one and (3-amino-4'-fluoro-biphenyl-4-yl)-carbamic acid tert-buty\ ester. MS found for C29H28FN3O2S as (M+H)+ 502.24. 1U NMR (400MHz, dmso-d6): δ:9.63 (s, IH), 7.91 (d, / =8.4Hz, 2H), 7.54-7.44 (m, 5H), 7.25 (dd, / =8.4,6.4Hz, IH), 7.17 (t, / =8.8Hz, 2H), 6.81 (d, / =8.2Hz, IH), 5.05 (s, 2H), 3.71-3.68 (m, 2H), 3.59-3.54 (m, 2H), 2.54-2.50 (m, 2H), 2.31- 2.26 (m, 2H), 2.22 (s, 3H), 2.20 (s, 3H). EXAMPLE 63
[0273] N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(5-methylthiazol-2-yl)tetrahydropyran-4- yl)benzamide
Figure imgf000116_0002
Example 63 (Compound a"0-37) [0274] Similar procedure from Example 9 was followed to obtain the title compound using
2-chloro-l,l-dimethoxy-propane. MS found for C28H26FN3O2S as (M+H)+ 488.35. 1H NMR Attorney Docket No. 8493-000092/WO/POA
(400MHz, dmso-d6): δ: 9.63 (s, IH), 7.91 (d, / =8.4Hz, 2H), 7.54-7.44 (m, 5H), 7.38 (s, IH), 7.26-7.23 (m, IH), 7.17 (t, / =8.8Hz, 2H), 6.81 (d, / =8.4Hz, IH), 5.05 (s, 2H), 3.73-3.70 (m, 2H), 3.58-3.53 (m, 2H), 2.57-2.53 (m, 2H), 2.34 (s, 3H), 2.31-12.29 (m, 2H). EXAMPLE 64
[0275] N-(2-amino-5-thiophen-2-yl-phenyl)-4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)- benzamide:
Figure imgf000117_0001
Example 64 (Compound a"0-12)
[0276] Methyl 4-(cyanomethyl)-benzoic acid methyl ester (1.92g, 11.01 mmol) and l-bromo-2-(2-bromo-ethoxy)-ethane (12.56 rnL, 55.04 mmol) were combined in THF (15 mL) and cooled down to 0 0C. Potassium bis(trimethylsilyl)-amide (0.5M in toluene, 48.3 mL, 24.21 mmol, 2.2 eq) was added over a period of 15 minutes and then warmed up to room temperature and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried with MgSO4 and evaporated under vacuum. The crude product was purified by chromatography on silica gel (25% EtOAc/hexanes) to afford 4-(4-cyano-tetrahydro- pyran-4-yl)-benzoic acid methyl ester. To a solution of 4-(4-cyano-tetrahydro-pyran-4-yl)- benzoic acid methyl ester (1.55g 6.32 mmol) in MeOH (10 mL) was added Et3N (3 mL). H2S was bubbled into the solution. The reaction vessel was stirred at room temperature for 3 days. The reaction mixture was then evaporated and purified by silica gel chromatography (33% EtOAc/hexanes) to afford 4-(4-thiocarbamoyl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester. [0277] The above compound was dissolved in DMF. Chloro-acetaldehyde in water (1.2 eq) was added and heated with microwave at 85 0C for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried with MgSO4 and evaporated under vacuum. This product was used for next step without purification. The solid 4-[4-(4- hydroxy-4,5-dihydro-thiazol-2-yl)-tetrahydro-pyran-4-yl] -benzoic acid methyl ester was dissolved in MeOH and an excess of p-TsOH was added and heated in the microwave for 20 minutes at 70 0C. The reaction mixture was diluted with EtOAc and washed with saturated Attorney Docket No. 8493-000092/WO/POA
NaHCCb solution. The organic phase was dried with MgSO4, evaporated under vacuum and purified by silica gel chromatography (33% EtOAc/hexanes).
[0278] Compound 4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (1.00 g, 3.3 mmol) was dissolved in MeOH (5 mL) and treated with IN NaOH. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution mixture was evaporated, suspended in water, and acidified with IN HCl. 4-(4-thiazol-2-yl- tetrahydro-pyran-4-yl)-benzoic acid was collected as precipitate, dried under vacuum, and used for next step without further purification.
[0279] A solution of 4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoic acid (0.9 g, 3.11 mmol), 2-Amino-4-thiophen-2-yl-phenyl-carbamic acid tert-butyl ester (1.08 g, 1.1 eq), HATU (1.42g, 1.2 eq), and DIPEA (1.04 mL, 2.0 eq) were dissolved in DMF and stirred at 45 0C overnight. After the reaction was complete, it was cooled down and precipitated with water and a saturated solution of NaHCO3. The solid formed was collected and used for next step without further purification. Solid {2-[4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzoylamino]-4- thiophen-2-yl-phenyl}-carbamic acid tert-butyl ester was re-dissolved in DCM/TFA (1:1) and stirred for 1 hour. After the reaction was complete, the reaction mixture was evaporated and purified by reverse phase chromatography to afford title compound, Example 64. MS found for C28H26N7FOS as (M+H)+ 461.12. 1H NMR (400MHz, dmso-d6): 1H-NMR (DMSO) δ: 9.74 (s, IH), 8.04 (d, J=8.0Hz, 2H), 7.67 (d, J=8.8Hz, 2H ), 7.44 (s, IH), 7.32 (d, J=5.2Hz, IH), 7.27 (d, J=8.4Hz, IH), 7.21 (d, J=3.6Hz, IH), 7.01 (q, J=3.6, 4.8Hz, IH ), 6.78 (d, J=8.4Hz, IH), 5.14 (s, IH), 4.02-4.00 (m, 2H), 3.69-3.65 (m, 2H), 2.11-2.08 (m, 4H). EXAMPLE 65
[0280] N-(4-amino-4'-fluoro-biphenyl-3-yl)-4-[4-(4-cyclopropyl-thiazol-2-yl)-tetrahydro- pyran-4-yl]-benzamide:
Figure imgf000118_0001
Example 65 (Compound a"0-44) Attorney Docket No. 8493-000092/WO/POA
[0281] Similar procedure from Example 64 was followed to obtain the title compound using 2-bromo-l-cyclopropyl-ethanone instead of 3-chloro-butan-2-one. MS found for C30H28FN3O2S as (M+H)+ 514.35. 1U NMR (400MHz, dmso-d6): δ: 9.84 (s, IH), 7.93 (d, / =8.0Hz, 2H), 7.58- 7.54 (m, 2H), 7.52-7.51 (m, 3H), 7.34 (dd, / =8.4,6.4Hz, IH), 7.20 (t, / =8.8Hz, 2H), 7.13 (s, IH) 6.96 (d, / =8.4Hz, IH), 3.71-3.68 (m, 2H), 3.57-3.52 (m, 2H), 2.56-2.52 (m, 2H), 2.35-2.29 (m, 2H), 2.03-1.98 (m, IH), 0.89-0.84 (m, 2H), 0.77-0.74 (m, 2H). EXAMPLE 66
[0282] 4-[4-(5-acetyl-4-methyl-thiazol-2-yl)-tetrahydro-pyran-4-yl]-N-(4-amino-4'-fluoro- biphenyl-3-yl)-benzamide:
Figure imgf000119_0001
-| 0 Example 66 (Compound a"0-46)
[0283] Similar procedure from Example 64 was followed to obtain the title compound using 3-chloro-pentane-2,4-dione instead of 3-chloro-butan-2-one. MS found for C30H28FN3O3S as (M+H)+ 530.41. 1H NMR (400MHz, dmso-d6): δ: 9.66 (s, IH), 7.95 (d, / =8.4Hz, 2H), 7.58- 7.51 (m, 4H), 7.44 (s, IH), 7.26 (dd, / =8.4,6.4Hz, IH), 7.17 (t, / =8.8Hz, 2H), 6.81 (d, / =8.4Hz,
15 IH), 5.06 (s, 2H), 3.70-3.67 (m, 2H), 3.62-3.57 (m, 2H), 2.62-2.47 (m, 2H), 2.61 (s, 3H), 2.42 (s,3H). EXAMPLE 67
[0284] 4-[4-(5-methyl-2H-[l,2,4]triazol-3-yl)-tetrahydro-pyran-4-yl]-benzoic acid 4-amino- 4'-fluoro-biphenyl-3-yl ester: Attorney Docket No. 8493-000092/WO/POA
Figure imgf000120_0001
Example 67 (Compound r-02)
[0285] 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (300 mg, 1.22 mmol) was suspended in water and then 4N NaOH was added and heated at 110 0C for 15 minutes. To this solution 2N HCl was added to precipitate the product. The solid was filtered out and used for next step without further purification. 4-(4-carbamoyl-tetrahydro-pyran-4-yl)-benzoic acid (200 mg, 0.80 mmol) was dissolved in DMF and then DMA-acetal in excess was added. The mixture was heated at 50 0C for 20 minutes. The reaction mixture was evaporated and used for next step without further purification. 4-[4-(l-dimethylamino-ethylidenecarbamoyl)-tetrahydro- pyran-4-yl] -benzoic acid methyl ester (50 mg, 0.150 mmol) and hydrazine hydrate (0.015 mL, 2 eq) were dissolved in AcOH and heated at 50 0C for 20 minutes. The reaction mixture was evaporated and used for next step without further purification. Hydrolysis HATU coupling, and amine de-protection was carried out following the same procedures from Example 64 using (3- amino-4'-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester instead of (2-amino-4-thiophen-2- yl-phenyl)-carbamic acid tert-butyl ester. MS found for C27H25FN4O3 as (M+H)+ 473.21. 1H NMR (400MHz, dmso-d6): δ:13.31 (s, IH), 9.55 (s, IH), 7.82 (d, / =7.6Hz, 2H), 7.50 (dd, / =8.8,5.2Hz, 2H), 7.41 (s, IH), 7.35 (d, / =8.4Hz, 2H), 7.20 (dd, / =8.0-2.4Hz, IH), 7.14 (t, / =8.8Hz, 2H), 6.77 (d, / =6.77Hz, IH), 5.00 (s, 2H), 3.73-3.71 (m, 2H), 3.37-3.31 (m, 2H), 2.58- 2.55 (m, 2H), 2.24 (s, 3H), 2.06-2.03 (m, 2H). EXAMPLE 68 [0286] N-(4-amino-4'-fluoro-biphenyl-3-yl)-4-(l-pyridin-2-yl-cyclopropyl)-benzamide: Attorney Docket No. 8493-000092/WO/POA
Figure imgf000121_0001
Example 68 (Compound e-01 )
[0287] Similar procedure from Example 49 was followed to obtain the title compound using 4-(l-cyano-cyclopropyl)-benzoic acid methyl ester instead of 4-(4-cyano-tetrahydro-pyran-4-yl)- benzoic acid methyl ester. MS found for C27H22FN3OaS (M+H)+ 424.31. 1H NMR (400MHz, dmso-dβ): δ:9.57 (s, IH), 8.34 (dd, / =4.8,1.2Hz, IH), 7.86 (d, J=8.0Hz, 2H), 7.44-7.40 (m, 3H), 7.35-7.33 (m, 3H), 7.15 (dd, / =8.0-2.0Hz, IH), 7.08-6.99 (m, 3H), 6.72-6.67 (m, 2H), 4.95 (s, 2H), 1.46-1.43 (m, 2H), 1.17-1.15 (m, 2H). EXAMPLE 69
[0288] 4-[l-(5-acetyl-4-methyl-thiazol-2-yl)-cyclopropyl]-N-(2-amino-phenyl)-benzamide:
Figure imgf000121_0002
-| 0 Example 69 (Compound aθ-115)
[0289] Similar procedure from Example 64 and Example 66 was followed to obtain the title compound. MS found for C22H2iN3O2S as (M+H)+ 392.28. 1H NMR (400MHz, CD3OD): 1H- NMR (CD3OD) δ:8.03 (d, / =8.2Hz, 2H), 7.64 (d, / =8.4Hz, 2H), 7.20 (d, / =7.6Hz, IH), 7.08 (d, / =8.4Hz, IH), 6.91 (d, / =8.0Hz, IH), 6.77 (t, / =7.2Hz, IH), 2.62 (s, 3H), 2.40 (s, 3H), 15 1.85-1.84 (m, 2H), 1.57-1.56 (m, 2H). EXAMPLE 70
[0290] N-(2-amino-phenyl)-4-[l-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)- cyclopropyl] -benzamide:
Figure imgf000121_0003
Example 70 (Compound aO-49) Attorney Docket No. 8493-000092/WO/POA
[0291] Similar procedure from Example 29 was followed to obtain the title compound using 4-(l-cyano-cyclopropyl)-benzoic acid methyl ester instead of 4-(4-cyano-tetrahydro-pyran-4-yl)- benzoic acid methyl ester. MS found for C23H24N4OS as (M+H)+ 405.32. 1U NMR (400MHz, dmso-dβ): 1H-NMR (CD3OD) δ: 8.32 (s, IH), 7.97 (d, / =8.8Hz, 2H), 7.56 (d, / =8.4Hz, 2H), 7.17 (d, / =6.4Hz, IH), 7.08-7.04 (m, IH), 6.89 (dd, / =8.0,7.2Hz, IH), 6.77-6.73 (m, IH), 3.74 (s, 2H), 2.99-2.96 (m, 2H), 2.89-2.86 (m, 2H), 2.56 (s, 3H), 1.70-1.68 (m, 2H), 1.49-1.46 (m, 2H). EXAMPLE 71
[0292] 4-[l-(5-acetyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-cyclopropyl]-N-(2- amino-phenyl)-benzamide:
Figure imgf000122_0001
Example 71 (Compound aO-53)
[0293] Similar procedure from Example 27 was followed to obtain the title compound using 4-(l-cyano-cyclopropyl)-benzoic acid methyl ester instead of 4-(4-cyano-tetrahydro-pyran-4-yl)- benzoic acid methyl ester. MS found for C24H24N4O2S as (M+H)+ 433.18. 1U NMR (400MHz, CD3OD): δ:7.95 (d, / =8.2Hz, 2H), 7.55 (d, / =8.2Hz, 2H), 7.18 (d, / =7.2Hz, IH), 7.08 (t, / =7.0Hz, IH), 6.88 (d, / =7.6Hz, IH), 6.76 (t, / =6.0Hz, IH), 4.63 (s, 3H), 3.91-3.76 (m, 2H), 2.85-2.73 (m, 2H), 2.19-2.11 (m, 2H), 1.73-1.67 (m, 2H), 1.50-1.43 (m, 2H). EXAMPLE 72
[0294] N-(4-amino-4'-fluoro-biphenyl-3-yl)-4-{4-[4,6-bis-(l-hydroxy-l-methyl-ethyl)- pyridin-2-yl] -tetrahydro-pyran-4-yl } -benzamide:
Figure imgf000122_0002
Example 72 (Compound e-08) Attorney Docket No. 8493-000092/WO/POA
[0295] Similar procedure from Example 49 was followed to obtain the title compound using 2-methyl-but-3-yn-2-ol and (3-amino-4'-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester instead of ethynyl-trimethyl-silane and (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert- butyl ester respectively. MS found for C35H38FN3O4 as (M+H)+ 584.36. 1U NMR (400MHz, dmso-dβ): δ:9.58 (s, IH), 7.86 (d, / =8.4Hz, 2H), 7.53-7.48 (m, 5H), 7.43 (s, IH), 7.25-7.23 (m, 2H), 7.16 (t, / =9.2Hz, 2H), 6.81 (d, / =8.4Hz, IH), 5.12 (s, 2H), 5.10 (s, IH), 5.03 (s, 2H), 3.69- 3.65 (m, 2H), 3.47-3.42 (m, 2H), 2.76-2.73 (m, 2H), 2.31-2.26 (m, 2H), 1.41 (s, 6H), 1.32 (s, 6H). EXAMPLE 73
[0296] N-(2-Amino-phenyl)-4-[l-(5-isopropyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2- yl)-cyclopropyl]-benzamide
Figure imgf000123_0001
Example 73 (Compound aO-51) [0297] Similar procedure from Example 29 was followed to obtain the title compound using
4-(l-cyano-cyclopropyl)-benzoic acid methyl ester and acetone instead of 4-(4-cyano-tetrahydro- pyran-4-yl)-benzoic acid methyl ester and p-formaldehyde, respectively. MS found for C25H28N4OSaS (M+H)+ 433.65. 1U NMR (400MHz, CD3OD): δ:8.43 (s, IH), 7.96 (d, / =8.4Hz,
2H), 7.55 (d, / =8.4Hz, 2H), 7.17 (d, / =8.2Hz, IH), 7.08-7.04 (m, IH), 6.90 (d, / =8.0Hz, IH),
6.77 (t, / =1.6Hz, IH), 3.82 (s, 2H), 3.11-3.02 (m, 2H), 2.86-2.83 (m, 2H), 1.70-1.67 (m, 2H),
1.49-1.46 (m, 2H), 1.17 (d, J=6.4Hz, 6H).
EXAMPLE 74 [0298] N-(2-aminophenyl)-4-(4-(5-(pyridin-3-yl)thiazol-2-yl)-tetrahydro-2H-pyran-4- yl)benzamide:
Figure imgf000123_0002
Example 7 '4 (Compound a"0-39)
[0299] Similar procedure from Example 51 was followed to obtain the title compound using fert-butyl-2-(4-(4-(5-(pyridin-3-yl)thiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzamido)-4- (thiophen-2-yl)phenylcarbamate and 1,2-phenylenediamine. MS found for C26H24N4SO2 as Attorney Docket No. 8493-000092/WO/POA
(M+H)+ 456.98. 1H NMR (400MHz, dmso-d6): δ 9.59 (brs, IH); 8.81 (d, / = 2.0 Hz, IH); 8.49 (d, / = 3.2 Hz, IH); 8.24 (s, IH); 7.99 (d, / = 8.4 Hz, IH); 7.94 (d, / = 8.4 Hz, 2H); 7.57 (d, / = 8.4 Hz, 2H); 7.42-7.41 (m, IH); 7.12 (d, / = 7.6 Hz, IH); 6.94 (t, / = 7.2 Hz, IH); 6.74 (d, / = 7.2 Hz, IH); 6.55 (t, / = 7.2 Hz, IH); 3.76-3.73 (m, 2H); 3.65-3.60 (m, 2H); 2.65-2.62 (m, 2H) ; 2.43-2.38 (m, 2H). EXAMPLE 75
[0300] N-(2-aminophenyl)-4-(4-(5-(6-cyclopropylpyridin-3-yl)thiazol-2-yl)-tetrahydro-2H- pyran-4-yl)benzamide:
Figure imgf000124_0001
Example 75 (Compound a"0-42) [0301] A mixture of 2-cyclopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
(490 mg, 2.00 mmol), methyl 4-(4-(5-bromothiazol-2-yl)-tetrahydro-2H-pyran-4-yl)benzoate (382 mg, 1.00 mmol), potassium carbonate (276 mg, 2.0 mmol), and 1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 146 mg, 0.20 mmol) in toluene/ethanol/water (2 mL/1 mL/1 mL) was heated in microwave (Emry's Optimizer) at 110 C for 20 minutes. The reaction mixture was cooled to room temperature and then diluted with EtOAc and filtered. The filtrate was concentrated and purified by Flash Chromatography (SiO2, 95%EtOAC:5% MeOH) to give methyl 4-(4-(5-(6-cyclopropylpyridin-3-yl)thiazol-2-yl)- tetrahydro-2H-pyran-4-yl)benzoate. MS found for C24H24N2O3S as (M+H)+ 421.42. To the above ester in MeOH/THF/dioxane (1:1:1) (9 mL) was added 3N NaOH (5.0 mL) and stirred at 55 0C. After 14 hours, the reaction mixture was concentrated, diluted with water, and neutralized with 6N HCl. The formed solids were filtered and washed with water and dried. MS found for C23H22N2O3S as (M+H)+ 407.04. The acid was used further without purification.
[0302] To the above carboxylic acid (406 mg, 1.0 mmol) in DMF (3 mL), was added HATU (570 mg, 1.5 mmol), 1,2-phenylenediamine (162 mg, 1.5 mmol) and NMM (0.4 mL) and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound, after lyophilization. MS found for C29H28N4SO2 as (M+H)+ 496.92. 1U NMR (400MHz, dmso-d6): δ 9.58 (s, IH); 8.60 Attorney Docket No. 8493-000092/WO/POA
(d, / = 2.0 Hz, IH); 8.13 (s, IH); 7.93 (d, /= 8.4 Hz, 2H); 7.83 (dd, / = 8.0, 2.0 Hz, 2H); 7.56 (d, / = 8.4 Hz, 2H); 7.30 (d, / = 8.0 Hz, 2H); 7.12 (d, / = 7.6 Hz, IH); 6.93 (d, / = 7.2 Hz, IH); 6.74 (d, / = 7.6 Hz, IH); 6.57 (d, / = 7.2 Hz, IH); 4.90 (brs, 2H); 3.75-3.72 (m, 2H); 3.63-3.59 (m, 2H); 2.64-2.62 (m, 2H) ; 2.46-2.36 (m, 2H); 2.09-2.05 (m, IH); 0.96-0.88 (m, 4H). EXAMPLE 76
[0303] N-(2-amino-phenyl)-4-[4-(4-pyrazin-2-yl-lH-imidazol-2-yl)-tetrahydro-pyran-4-yl]- benzamide:
Figure imgf000125_0001
Example 76 (Compound q-01 )
[0304] 4-(4-Cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (l.Og, 4.08 mmol) was suspended in 4.0N NaOH and heated at 110 0C for 1 hour. After the reaction was complete, 2N HCl was slowly added to form a precipitate. The precipitate was then filtered, dried under vacuum, and used for next step without purification. 4-(4-Carboxy-phenyl)-tetrahydro-pyran-4- carboxylic acid (0.4g, 1.6 mmol) was dissolved in NMP. HATU (1.28 g, 2.1 eq) and DIPEA (0.8 mL, 3.0 eq) were added and stirred at 50 0C for 1 hour. The reaction mixture was cooled down to room temperature and benzyl alcohol (172 mg, 1.0 eq) was added. The reaction mixture was stirred at room temperature overnight. Saturated aqueous solution of NaHCO3 was added to the mixture and was then extracted with EtOAc. The organic phase was dried, evaporated and used for next step without further purification.
[0305] To a solution of 4-(4-benzyloxycarbonyl-phenyl)-tetrahydro-pyran-4-carboxylic acid (0.3g, 0.88 mmol) and 2-bromo-l-pyrazin-2-yl-ethanone (210 mg, 1.2 eq) in acetonitrile, TEA (0.18 mL, 1.2 eq) was added and heated in the microwave at 80 0C for 1 hour. The reaction mixture was evaporated and purified by silica gel chromatography (Hex:EtOAc 25:75). 4-(4- benzyloxycarbonyl-phenyl)-tetrahydro-pyran-4-carboxylic acid 2-oxo-2-pyrazin-2-yl-ethyl ester (0.3g, 0.65 mmol), NH4OAc (110 mg, 2.2 eq) and 3A molecular sieves were mixed together in xylene and heated in the microwave at 160 0C for 1 hour. After the reaction was done, it was extracted with EtOAc and the organic phase was dried and evaporated to be used in the next step without further purifications. Attorney Docket No. 8493-000092/WO/POA
[0306] Hydrogenation of 4-[4-(4-pyrazin-2-yl-lH-imidazol-2-yl)-tetrahydro-pyran-4-yl]- benzoic acid benzyl ester (0.2 mg, 0.45 mmol) in EtOH, was carried out in the presence of excess Pd/C (10%, dry basis) at a pressure of 1 atmosphere. After 16 hours, the reaction mixture was filtered through a celite pad and washed with hot ethanol. The solution was evaporated and used for next step without further purification.
[0307] The above acid was then coupled with 1,2-phenylenediamine in the presence of HATU and DIPEA in DMF and purified by reverse phase chromatography to give the title compound. MS found for C25H24N6O2 as (M+H)+ 441.21 1H NMR (400MHz, dmso-d6): 1H- NMR (DMSO) δ: 10.42 (s, IH), 9.32 (s, IH), 8.68-8.64 (m, 2H), 8.37 (s, IH), 8.07 (d, J=SAHz, 2H), 7.54 (d, J=SAHz, 2H ), 7.46-7.28 (m, 5H), 3.82-3.79 (m, 2H), 3.52-3.46 (m, 2H), 2.98-2.95 (m, 2H), 2.40-2.29 (m, 2H). EXAMPLE 77
[0308] N-(2-amino-phenyl)-4-[4-(4-phenyl-lH-imidazol-2-yl)-tetrahydro-pyran-4-yl]- benzamide:
Figure imgf000126_0001
Example 77 (Compound q-04)
[0309] Similar procedure from Example 76 was followed to obtain the title compound using 2-bromo-l-phenyl-ethanone. MS found for C27H26N4O2 as (M+H)+ 439.04 1H NMR (400MHz, dmso-d6): 1H-NMR (DMSO) δ: 10.15 (s, IH), 8.09 (s, IH), 8.05(d, /=8.4Hz, 2H), 7.86 (d, /=7.2Hz, 2H ), 7.55 (d, /=8.4Hz, 2H), 7.49-7.33 (m, 4H), 7.15 (d, /=6.4Hz, 2H), 7.04 (s, IH), 3.82-3.79 (m, 2H), 3.53-3.48 (m, 2H), 2.97-2.90 (m, 2H), 2.41-2.38 (m, 2H). EXAMPLE 78
[0310] N-(2-amino-phenyl)-4-[4-(l-methyl-4-pyrazin-2-yl-lH-imidazol-2-yl)-tetrahydro- pyran-4-yl]-benzamide: Attorney Docket No. 8493-000092/WO/POA
Figure imgf000127_0001
Example 78 (Compound q-02)
[0311] 4-(4-Cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (l.Og, 4.08 mmol) was suspended in 4.0N NaOH and heated at 110 0C for 1 hour. After the reaction was completed, 2N HCl was slowly added to form a precipitate. The precipitate was then filtered, dried under vacuum, and used for next step without purification.
[0312] 4-(4-carboxy-phenyl)-tetrahydro-pyran-4-carboxylic acid (0.4g, 1.6 mmol) was dissolved in NMP and then HATU (1.28 g, 2.1 eq) and DIPEA (0.8 mL, 3.0 eq) were added and stirred at 50 0C for 1 hour. The reaction mixture was cooled down to room temperature and benzyl alcohol (172 mg, 1.0 eq) was added. The reaction mixture was stirred at room temperature overnight. A saturated aqueous solution of NaHCO3 was added to the mixture and was then extracted with EtOAc. The organic phase was dried, evaporated and used for next step without further purification.
[0313] To a solution of 4-(4-benzyloxycarbonyl-phenyl)-tetrahydro-pyran-4-carboxylic acid (0.3g, 0.88 mmol) and 2-bromo-l-pyrazin-2-yl-ethanone (210 mg, 1.2 eq) in acetonitrile, TEA (0.18 mL, 1.2 eq) was added and heated in the microwave at 80 0C for 1 hour. The reaction mixture was evaporated and purified by silica gel chromatography (Hex:EtOAc 25:75). 4-(4- benzyloxycarbonyl-phenyl)-tetrahydro-pyran-4-carboxylic acid 2-oxo-2-pyrazin-2-yl-ethyl ester (0.3g, 0.65 mmol), NH4OAc (110 mg, 2.2 eq) and 3A molecular sieves were mixed together in xylene and heated in the microwave at 160 0C for 1 hour. After the reaction was done, it was extracted with EtOAc and the organic phase was dried and evaporated to be used in the next step without further purifications.
[0314] 4-[4-(4-pyrazin-2-yl-lH-imidazol-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid benzyl ester (168 mg, 0.38 mmol) was dissolved in THF (3 mL). MeI (0.26 mL, 1.1 eq) and NaH (10 mg, 1.1 eq) were added at room temperature under vigorous stirring. After one hour, the mixture was evaporated under vacuum and then extracted in EtOAc. The organic phase was dried and evaporated to be used for next step. Hydrogenation of 4-[4-(l-methyl-4-pyrazin-2-yl-lH- imidazol-2-yl)-tetrahydro-pyran-4-yl] -benzoic acid benzyl ester (0.2 mg, 0.44 mmol) in EtOH Attorney Docket No. 8493-000092/WO/POA
was carried out in the presence of excess Pd/C (10%, dry basis) at a pressure of 1 atmosphere. After 16 hours, the reaction mixture was filtered through a celite pad and washed with hot ethanol. The solution was evaporated and used for next step without further purification.
[0315] The above acid was then coupled with 1,2-phenylenediamine in the presence of HATU and DIPEA in DMF and purified by reverse phase chromatography to give the title compound. MS found for C26H26N6O2 as (M+H)+ 455.08 1H NMR (400MHz, dmso-d6): 1H- NMR (DMSO) δ: 10.44 (s, IH), 9.14 (d, /=1.6Hz, IH), 8.54-8.53 (m, IH), 8.44 (d, /=2.4Hz, IH), 8.05 (d, /=8.4Hz, 2H), 7.82 (s, IH), 7.47-7.29 (m, 6H), 3.79-3.78 (m, 4H), 3.20 (s, 3H), 2.56- 2.20 (m, 4H). EXAMPLE 79
[0316] N-(2-amino-phenyl)-4-[4-(l-methyl-4-phenyl-lH-imidazol-2-yl)-tetrahydro-pyran-4- yl]-benzamide
Figure imgf000128_0001
Example 79 (Compound q-05)
[0317] Similar procedure from Example 78 was followed to obtain the title compound using 2-bromo-l-phenyl-ethanone. MS found for C28H28N4O2 as (M+H)+ 453.17 1H NMR (400MHz, dmso-d6): 1H-NMR (DMSO) δ: 10.49 (s, IH), 8.11 (d, J=SAUz, 2H), 7.81-7.79 (m, 3H), 7.48- 7.25 (m, 9H), 3.74-3.66 (m, 4H), 3.32 (s, 3H), 2.66-2.43 (m, 4H). EXAMPLE 80: BIOLOGICAL ASSAYS
[0318] HDAC inhibitory activity of the compound of Example 1 was measured by two types of assays in which HDAC 1 and 6 were used as a target molecule. The first assay was carried out without preincubation after addition of the enzyme. The test compound was suspended in and titrated in DMSO. It was then spotted into a 384-well test plate. The enzyme, HDAC 1 or 6, was diluted in assay buffer containing 25mM Tris-HCl (pH 8.0), 137mM NaCl, 2.7mM KCl, and
0.01% Tween-20 and added to the pre-spotted compound. The peptide substrate containing a fluorophore/quencher pair was diluted in the same assay buffer and added to the compound/enzyme mix initiating the reaction. The reaction incubated at room temperature for about 45 minutes. A concentrated developer solution was diluted in the assay buffer, and added Attorney Docket No. 8493-000092/WO/POA
to the reaction. The reaction was incubated at room temperature for about 15 minutes and relative fluorescence was read on an instrument reader.
[0319] The second assay is similar to the first assay described above, except that preincubation is carried out for about 3 hours after the enzyme is introduced. The test compound was suspended in, and titrated in DMSO. It was then spotted into a 384-well test plate. The enzyme, HDAC 1 or 6, was diluted in the same assay buffer as used in the previous assay and added to the pre-spotted compound. The enzyme/compound mix was incubated at room temperature for about 3 hours. The peptide substrate containing a fluorophore/quencher pair was diluted in the assay buffer and added to the compound/enzyme mix initiating the reaction. The reaction incubated at room temperature for 45 minutes. A concentrated developer solution was diluted in the assay buffer, and added to the reaction. The reaction was incubated at room temperature for about 15 minutes and relative fluorescence was read on an instrument reader.
[0320] Table 6 shows IC50 data for the compound tested with the protocols described above. Table 6. IC50 of HDAC inhibitor compounds
Figure imgf000129_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000130_0001
[0321] The results indicate that the compounds have inhibitory activity against HDAC and thus can be useful to treat or inhibit diseases caused by abnormal activities of HDAC.
[0322] All patents and publications cited herein are incorporated by reference into this application in their entirety.

Claims

Attorney Docket No. 8493-000092/WO/POAWHAT IS CLAIMED IS:
1. A compound selected from those of Formula (I) and pharmaceutically acceptable salts thereof:
Figure imgf000131_0001
Formula (I) wherein
Cy1 is cycloalkylidene or heterocycloalkylidene; Cy2 is cycloalkyl, aryl or heterocyclyl; Ar is aryl or heteroaryl; m is an integer from 0 to the maximum number of substitutable positions on Ar; n is an integer from 0 to the maximum number of substitutable positions on Cy1; p is an integer equal to the number of substitutable positions on Cy2;
R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH, and aryl or heteroaryl is optionally further substituted with one or more groups selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl and haloheterocyclyl, wherein alkyl, alkenyl or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl;
R2 is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, trifluoromethyl, trifluoromethoxy, amino, carboxyl, carbamoyl, sulphamoyl, C1-1O alkyl,
C2-10 alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, N-(Ci-I0 alkyl)amino, N,N-(Cι-ιo alkyl)2 amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, N,N-(Ci_i0 alkyl)2 carbamoyl, C1-10 alkyl-S(O)a wherein a is 0, 1 or 2, NH2-S(O)2NH-, N-(C1-10 alkyl) sulphamoyl, MN-(C1-1O alkyl)2sulphamoyl, cycloalkyl, heterocyclyl and aryl; R3 is independently selected from the group consisting of halo, hydroxyl, oxo, nitro, cyano, trifluoromethyl, trifluoromethoxy, amino, carboxyl, carbamoyl, sulphamoyl, C1-1O alkyl, C2- io alkenyl, C2_i0 alkynyl, C1-1Q alkoxy, C1-1Q alkanoyl, N-(C1-1Q alkyl)amino, NjN-(C1-1Q Attorney Docket No. 8493-000092/WO/POA
alkyl)2 amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, N,N-(Ci_io alkyl)2 carbamoyl, Ci-io alkyl-S(O)a wherein a is 0, 1 or 2, NH2-S(O)2NH-, N-(C1-10 alkyl)sulphamoyl, N,N- (C1-1O alkyl)2sulphamoyl, cycloalkyl, heterocyclyl and aryl, wherein each R3 is optionally substituted by one or more A; or two groups R3 are substituted on the same carbon ring atom of Cy1 and together with the carbon ring atom of Cy1 form a ring situated on Cy1 in a spiro configuration, wherein the spiro ring is cycloalkyl or heterocycloalkyl;
R4 is independently selected from the group consisting of H, halo, nitro, cyano, hydroxyl, oxo, hydroxy(Ci_io alkyl), amino(Ci_io alkyl), haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, hydroxy(Ci_io alkoxy)(Ci_i0 alkoxy), (C1-10 alkoxy)(Ci_i0 alkoxy), (C1-10 alkoxy)(Ci_i0 alkyl), C1-10 alkanoyl, C1-10 alkanoyloxy, N-(C1-10 alkyl)amino, N,N-(C1-10 alkyl)2amino, Ci-io alkanoylamino, N-(C1-10 alkyl)carbamoyl, N,N-(C1-10 alkyl)2carbamoyl, C1-10 alkyl- S(O)a wherein a is 0, 1 or 2, C1-10 alkoxycarbonyl, NH2-S(O)2NH-, NH2-CO-NH-, N-(Ci-I0 alkyl)sulphamoyl, N,N-(C1-10 alkyl)2sulphamoyl, aryl, arylalkyl, aryloxy, arylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyl(C=O)-, heterocyclyloxy and heterocyclylthio, wherein if R4 is not aryl, cycloalkyl or heterocyclyl, each R4 is optionally substituted by one or more B, and if R4 is aryl, cycloalkyl or heterocyclyl, R4 is optionally further substituted by one or more R5, or when p is 2 or greater, two R4 groups form a 5- or 6-membered cyclic moiety to make a fused ring with Cy2 ring, wherein the cyclic moiety can contain one or more heteroatoms selected from Ν, O and S and the fused ring is optionally substituted by one or more R5;
R5 is independently selected from halo, nitro, cyano, hydroxyl, oxo, hydroxy(Ci_io alkyl), amino(Ci_io alkyl), haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, hydroxy(Ci-io alkoxy)(Ci_io alkoxy), (C1-10 alkoxy)(Ci_i0 alkoxy), (C1-10 alkoxy)(Ci_i0 alkyl), C1-10 alkanoyl, C1-10 alkanoyloxy, N-(C1-10 alkyl)amino, N,N-(C1-10 alkyl)2amino, C1-10 alkanoylamino, N-(C1-10 alkyl)carbamoyl, N,N-(C1-10 alkyl)2carbamoyl, C1-10 alkyl-S(O)a wherein a is 0, 1 or 2, C1-10 alkoxycarbonyl, NH2-S(O)2NH-, NH2-CO-NH-, N-(C1-10 alkyl)sulphamoyl, N,N-(C1-10 alkyl)2sulphamoyl, aryl, arylalkyl, aryloxy, arylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, Attorney Docket No. 8493-000092/WO/POA
heterocyclyl(C=O)-, heterocyclyloxy and heterocyclylthio, wherein each R5 is optionally substituted by one or more D; and
A, B and D are independently selected from halo, nitro, cyano, hydroxyl, oxo, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, NN-(C1-1O alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, NN-
(Ci-io alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-1O alkoxycarbonyl,
N-(Ci-I0 alkyl) sulphamoyl, NN-(C1-10 alkyl)2sulphamoyl, H2NS(O)2NH-,
N-(Ci-I0 alkyl)NHS(O)2NH-, N1N-(C1-10 alkyl)2ΝS(O)2ΝH-, aryl, aryloxy, arylthio, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyl(C=O)-, heterocyclyloxy and heterocyclylthio .
2. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein R1 is hydroxyl, phenyl or 5-membered or 6-membered heteroaryl, wherein phenyl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH- moiety, and phenyl or heteroaryl is optionally further substituted with one or more substituent selected from amino, halo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl, and haloheterocyclyl, wherein alkyl, alkenyl, or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl and cycloalkyl.
3. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein Cy1 is C3-? ccyyccllooaallkkyylliiddeene or heterocycloalkylidene having from 3 to 7 ring members; and Cy2 is heterocyclyl.
4. The compound or pharmaceutically acceptable salt thereof of Claim 1, wherein Cy2 is a 5-membered or 6-membered heteroaryl containing at least one N atom as hetero ring atom.
5. The compound or pharmaceutically acceptable salt thereof of Claim 1 selected from those of Formulae (I-a), (I-b), (I-c), and (I-d): Attorney Docket No. 8493-000092/WO/POA
Figure imgf000134_0001
Formula (l-b)
(l-d)
Figure imgf000134_0002
wherein m is 0, 1, 2, 3 or 4; Cy1 is C3_7 cycloalkylidene or heterocycloalkylidene;
R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, and aryl or heteroaryl is optionally further substituted with one or more substituent selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl, and haloheterocyclyl, wherein alkyl, alkenyl, or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; and each R4 is independently selected from H, halo, nitro, cyano, hydroxyl, hydroxy(Ci_io alkyl), haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, CMO alkyl, C2-10 alkenyl, C2-10 alkynyl, CMO alkoxy, CMO alkanoyl, CMO alkanoyloxy, iV-(Ci-io alkyl)amino, N,N-(Ci_io alkyl)2amino, CMO alkanoylamino, N-(Ci_io alkyl)carbamoyl, N,N-
(C1-1O alkyl)2carbamoyl, CMO alkyl-S(O)a wherein a is 0, 1 or 2, CMO alkoxycarbonyl,
NH2-S(O)2NH-, N-(Ci_io alkyl) sulphamoyl, -Y-V-(C1-10 alkyl)2sulphamoyl, aryl, cycloalkyl and heterocyclyl wherein if R4 is not aryl, cycloalkyl or heterocyclyl, each R4 is optionally substituted by one or more B, and if R4 is aryl, cycloalkyl or heterocyclyl, R4 is optionally further substituted by one or more R5, or when the compound is selected from Formula (I-a) and (I-b), p is 2 and two R4 groups are substituted at positions 4 and 5 of the thiazole ring and form a 5- or 6-membered cyclic Attorney Docket No. 8493-000092/WO/POA
moiety to make a fused ring with the thiazole ring, wherein the cyclic moiety can contain one or more heteroatoms selected from N, O and S and the fused ring is optionally substituted by one or more R5.
6. The compound or pharmaceutically acceptable salt thereof of Claim 5 which has Formula (I- aθ):
Figure imgf000135_0001
Formula (l-aθ) wherein R6 and R7 are independently selected from H, halo, nitro, cyano, hydroxyl, hydroxy(Ci_io alkyl), haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, NN-(C1-1O alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, NN-(C1-1O alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-1O alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-10 alkyl)sulphamoyl, and NN-(C1-10 alkyl)2sulphamoyl, or form a 5- or 6-membered cyclic moiety to make a fused ring with the thiazole ring, wherein the cyclic moiety can contain one or more heteroatoms selected from
Ν, O and S, wherein each R6 and R7 is optionally substituted by one or more B.
7. The compound of Claim 6 which is selected from the group consisting of:
4-(l-(5-acetyl-4-methylthiazol-2-yl)cyclopropyl)-N-hydroxybenzamide; 4-(l-(5-acetyl-4-methylthiazol-2-yl)cyclopropyl)-N-(2-aminophenyl)benzamide;
N-hydroxy-4-(l-(4-((2-methoxyethylamino)methyl)thiazol-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-((2-methoxyethylamino)methyl)thiazol-2- yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-((pyridin-2-ylamino)methyl)thiazol-2-yl)cyclopropyl)benzamide; N-(2-aminophenyl)-4-(l-(4-((pyridin-2-ylamino)methyl)thiazol-2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-((2,2,2-trifluoroethylamino)methyl)thiazol-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-((2,2,2-trifluoroethylamino)methyl)thiazol-2- yl)cyclopropyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
4-(l-(4-((cyclopropylmethylamino)methyl)thiazol-2-yl)cyclopropyl)-N-hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-((cyclopropylmethylamino)methyl)thiazol-2- yl)cyclopropyl)benzamide;
2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)-N,N,4-trimethylthiazole-5-carboxamide; 2-( 1 -(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)-N,N-4-trimethylthiazole-5- carboxamide;
2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)-N-isopropylthiazole-4-carboxamide;
2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)-N-isopropylthiazole-4-carboxamide;
N-hydroxy-4-(l-(4,5,6,7-tetrahydrobenzo[(i]thiazol-2-yl)cyclopropyl)benzamide; N-(2-aminophenyl)-4-(l-(4,5,6,7-tetrahydrobenzo[(i]thiazol-2-yl)cyclopropyl)benzamide; ethyl 2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridine-
5(4H)-carboxylate; ethyl 2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)-6,7-dihydrothiazolo[5,4- c]pyridine-5(4H)-carboxylate; N-hydroxy-4-(l-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2- yl)cyclopropyl)benzamide; tert-butyl 2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)-6,7-dihydrothiazolo[5,4- c]pyridine-5(4H)-carboxylate; and tert-butyl 2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)-6,7-dihydrothiazolo[5,4- c]pyridine-5(4H)-carboxylate;
N-(2-aminophenyl)-4-(l-(4-methylthiazol-2-yl)cyclopropyl)benzamide;
(5')-4-(l-(5-(2-amino-3-methylbutanoyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2- yl)cyclopropyl)-N-(2-aminophenyl)benzamide; N-(2-amino-5-fluorophenyl)-4-(l-(thiazol-2-yl)cyclopropyl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(l-(thiazol-2-yl)cyclopropyl)benzamide;
N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(l-(thiazol-2-yl)cyclopropyl)benzamide;
N-(2-amino-5-(5-methylthiophen-2-yl)phenyl)-4-(l-(thiazol-2-yl)cyclopropyl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(l-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridine-2-yl)cyclopropyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(l-(6,7-dihydropyrano[4,3-d]thiazol-2- yl)cyclopropyl)benzamide; and pharmaceutically acceptable salts thereof.
8. The compound or pharmaceutically acceptable salt thereof of Claim 5 which has a formula selected from the group consisting of:
(l-a2)
Figure imgf000137_0001
Figure imgf000137_0002
(l-a6) wherein R6', R7', R8, R9 and R10 are independently selected from H and the functional groups of R5, wherein each R6', R7', R8, R9 and R10 is optionally substituted by one or more D.
9. The compound of Claim 8 which is selected from the group consisting of:
N-hydroxy-4-(l-(4-(imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)benzamide; N-hydroxy-3-(l-(4-(imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(imidazo[l,2-α]pyridin-3-yl)-5-methylthiazol-2- yl)cyclopropyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
ΛMiydroxy-3-(l-(4-(imidazo[l,2-α]pyridin-3-yl)-5-methylthiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-3-(l-(4-(imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)benzamide; N-(2-aminophenyl)-4-(l-(4-(imidazo[l,2-α]pyridin-3-yl)-5-methylthiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-3-(l-(4-(imidazo[l,2-α]pyridin-3-yl)-5-methylthiazol-2- yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-hydroxy-3-(l-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(5-methyl-4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide; N-hydroxy-3-(l-(5-methyl-4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N- (2- aminophenyl)- 3 - ( 1 - (4-(2-methylimidazo [ 1 ,2-a] pyridin-3 - yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(5-methyl-4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-3-(l-(5-methyl-4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide; 4-(l-(4-(6-chloro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(6-chloro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(7-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-(2-aminophenyl)-4-(l-(4-(7-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
4-(l-(4-(7-((dimethylamino)methyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)-N- hydroxybenzamide; N-(2-aminophenyl)-4-(l-(4-(7-((dimethylamino)methyl)imidazo[l,2-α]pyridin-3-yl)thiazol-
2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(7-(pyrrolidin-l-ylmethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(pyrrolidin-l-ylmethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(7-(morpholinomethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(morpholinomethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide; N-hydroxy-4-(l-(4-(2-methyl-6-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-6-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-
2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(2-methyl-7-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-7-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-
2-yl)cyclopropyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-N-(2-methoxyethyl)-2- methylimidazo[l,2-α]pyridine-7-carboxamide; 3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-N-(2-methoxyethyl)-
2-methylimidazo[l,2-α]pyridine-7-carboxamide;
4-(l-(4-(7-cyano-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-cyano-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-7-carboxamide;
3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-7-carboxamide; methyl 3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylate; methyl 3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylate;
N-hydroxy-4-(l-(4-(2-methyl-7-(4-methylpiperazine-l-carbonyl)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-7-(4-methylpiperazine-l-carbonyl)imidazo[l,2- α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-2-methylimidazo[l,2- α]pyridine-7-carboxylic acid; 3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylic acid;
N-hydroxy-4-(l-(4-(2-methyl-7-(2-morpholinoethoxy)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-7-(2-morpholinoethoxy)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopropyl)benzamide;
4-(l-(4-(7-(2-(dimethylamino)ethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)-N-hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(2-(dimethylamino)ethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopropyl)benzamide; N-hydroxy-4-(l-(4-(7-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopropyl)benzamide;
4-(l-(4-(7-(2-(dimethylamino)ethylamino)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)-N-hydroxybenzamide; Attorney Docket No. 8493-000092/WO/POA
N-(2-aminophenyl)-4-(l-(4-(7-(2-(dimethylamino)ethylamino)-2-methylimidazo[l,2- α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-N-(2-methoxyethyl)-2- methylimidazo[l,2-α]pyridine-6-carboxamide; 3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-N-(2-methoxyethyl)-
2-methylimidazo[l,2-α]pyridine-6-carboxamide;
N-hydroxy-4-(l-(4-(2-methyl-6-(4-methylpiperazine-l-carbonyl)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-6-(4-methylpiperazine-l-carbonyl)imidazo[l,2- α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-6-carboxamide;
3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)thiazol-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-6-carboxamide; N-hydroxy-4-(l-(4-(6-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(6-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(6-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(6-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
4-(l-(4-(8-fluoro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)-N- hydroxybenzamide; N-(2-aminophenyl)-4-(l-(4-(8-fluoro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
4-(l-(4-(7-((dimethylamino)methyl)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)-N-hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-((dimethylamino)methyl)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopropyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
4-(l-(4-(6-bromo-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopropyl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(6-bromo-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(7-methoxy-2-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-methoxy-2-(trifluoromethyl)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopropyl)benzamide; and pharmaceutically acceptable salts thereof.
10. The compound or pharmaceutically acceptable salt thereof of Claim 5 which has a formula selected from the group consisting of:
Figure imgf000142_0001
(l-a12) wherein R \ 6ι', n Rli', R , R and R 1 10 are independently selected from H and the functional groups of R5, wherein each R6', R7', R8, R9 and R10 is optionally substituted by one or more D. Attorney Docket No. 8493-000092/WO/POA
11. The compound of Claim 10 which is selected from the group consisting of: N-hydroxy-4-(l-(4-(l-isopropyl-2-methylimidazol-5-yl)thiazol-2-yl)cyclopropyl)benzamide; N-(2-aminophenyl)-4-(l-(4-(l-isopropyl-2-methylimidazol-5-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(4-isopropyl-5-methyll,2,4-triazol-3-yl)thiazol-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(4-isopropyl-5-methyll,2,4-triazol-3-yl)thiazol-2- yl)cyclopropyl)benzamide; N-hydroxy-4-(l-(4-(pyridin-3-yl)thiazol-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(pyridin-3-yl)thiazol-2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(pyridin-4-yl)thiazol-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(pyridin-4-yl)thiazol-2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(pyridin-2-yl)thiazol-2-yl)cyclopropyl)benzamide; N-(2-aminophenyl)-4-(l-(4-(pyridin-2-yl)thiazol-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(pyrazin-2-yl)thiazol-2-yl)cyclopropyl)benzamide; and pharmaceutically acceptable salts thereof.
12. The compound or pharmaceutically acceptable salt thereof of Claim 5 which has a formula selected from the group consisting of:
),
Figure imgf000143_0001
Attorney Docket No. 8493-000092/WO/POA
q is 2, 3, 4, or 5;
R6 and R7 are independently H or the functional groups of R4, or form a 5- or 6-membered cyclic moiety to make a fused ring with the thiazole ring, wherein the cyclic moiety can contain one or more heteroatoms selected from N, O and S; wherein each R6 and R7 is optionally substituted by one or more B; and
R6', R7', R8, R9 and R10 are independently selected from H, halo, nitro, cyano, hydroxyl, hydroxy(Ci_io alkyl), haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, NN-(C1-1O alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, NN-(C1-1O alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-1O alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-1O alkyl) sulphamoyl, and N,N-(Ci_io alkyl)2sulphamoyl, wherein each R6', R7', R8, R9 and R10 is optionally substituted by one or more D
13. The compound of Claim 12 which is selected from the group consisting of:
N-hydroxy-4-(l-(4-(imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopentyl)benzamide;
N-hydroxy-4-(l-(4-(imidazo[l,2-α]pyridin-3-yl)-5-methylthiazol-2- yl)cyclopentyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopentyl)benzamide; N-(2-aminophenyl)-4-(l-(4-(imidazo[l,2-α]pyridin-3-yl)-5-methylthiazol-2- yl)cyclopentyl)benzamide;
N-hydroxy-4-(l-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-hydroxy-4-(l-(5-methyl-4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-(2-aminophenyl)-4-(l-(5-methyl-4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide; 4-(l-(4-(6-chloro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopentyl)-N- hydroxybenzamide; Attorney Docket No. 8493-000092/WO/POA
N-(2-aminophenyl)-4-(l-(4-(6-chloro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-hydroxy-4-(l-(4-(7-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide; N-(2-aminophenyl)-4-(l-(4-(7-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
4-(l-(4-(7-((dimethylamino)methyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopentyl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-((dimethylamino)methyl)imidazo[l,2-α]pyridin-3-yl)thiazol- 2-yl)cyclopentyl)benzamide;
N-hydroxy-4-(l-(4-(7-(pyrrolidin-l-ylmethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(pyrrolidin-l-ylmethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide; N-hydroxy-4-(l-(4-(7-(morpholinomethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(morpholinomethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-hydroxy-4-(l-(4-(2-methyl-6-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-6-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-
2-yl)cyclopentyl)benzamide;
N-hydroxy-4-(l-(4-(2-methyl-7-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide; N-(2-aminophenyl)-4-(l-(4-(2-methyl-7-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-
2-yl)cyclopentyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-N-(2-methoxyethyl)-2- methylimidazo[l,2-α]pyridine-7-carboxamide;
3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-N-(2-methoxyethyl)- 2-methylimidazo[l,2-α]pyridine-7-carboxamide; Attorney Docket No. 8493-000092/WO/POA
4-(l-(4-(7-cyano-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopentyl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-cyano-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide; 3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-7-carboxamide;
3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-7-carboxamide; methyl 3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylate; methyl 3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylate;
N-hydroxy-4-(l-(4-(2-methyl-7-(4-methylpiperazine-l-carbonyl)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopentyl)benzamide; N-(2-aminophenyl)-4-(l-(4-(2-methyl-7-(4-methylpiperazine-l-carbonyl)imidazo[l,2- α]pyridin-3-yl)thiazol-2-yl)cyclopentyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-2-methylimidazo[l,2- α]pyridine-7-carboxylic acid;
3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-2-methylimidazo[l,2- α]pyridine-7-carboxylic acid;
N-hydroxy-4-(l-(4-(2-methyl-7-(2-morpholinoethoxy)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-7-(2-morpholinoethoxy)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopentyl)benzamide; 4-(l-(4-(7-(2-(dimethylamino)ethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)-N-hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(2-(dimethylamino)ethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopentyl)benzamide;
N-hydroxy-4-(l-(4-(7-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-(2-aminophenyl)-4-(l-(4-(7-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopentyl)benzamide;
4-(l-(4-(7-(2-(dimethylamino)ethylamino)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)-/V-hydroxybenzamide; N-(2-aminophenyl)-4-(l-(4-(7-(2-(dimethylamino)ethylamino)-2-methylimidazo[l,2- α]pyridin-3-yl)thiazol-2-yl)cyclopentyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-N-(2-methoxyethyl)-2- methylimidazo[l,2-α]pyridine-6-carboxamide;
3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-N-(2-methoxyethyl)- 2-methylimidazo[l,2-α]pyridine-6-carboxamide;
N-hydroxy-4-(l-(4-(2-methyl-6-(4-methylpiperazine-l-carbonyl)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopentyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-6-(4-methylpiperazine-l-carbonyl)imidazo[l,2- α]pyridin-3-yl)thiazol-2-yl)cyclopentyl)benzamide; 3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-6-carboxamide;
3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopentyl)thiazol-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-6-carboxamide;
N-hydroxy-4-(l-(4-(6-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(6-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopentyl)benzamide;
N-hydroxy-4-(l-(4-(6-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide; N-(2-aminophenyl)-4-(l-(4-(6-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
4-(l-(4-(8-fluoro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopentyl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(8-fluoro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
4-(l-(4-(7-((dimethylamino)methyl)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)-./V-hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-((dimethylamino)methyl)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopentyl)benzamide;
4-(l-(4-(6-bromo-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)cyclopentyl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(6-bromo-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-hydroxy-4-(l-(4-(7-methoxy-2-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)cyclopentyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-methoxy-2-(trifluoromethyl)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)cyclopentyl)benzamide;
N-(2-Amino-phenyl)-4-[l-(4-pyridin-3-yl-thiazol-2-yl)-cyclopentyl]-benzamide; and pharmaceutically acceptable salts thereof.
14. The compound or pharmaceutically acceptable salt thereof of Claim 5 which has a formula selected from the group consisting of:
(l-a"0),
Figure imgf000148_0001
Formula (l-a"1 ),
Figure imgf000148_0002
Formula (l-a"2),
Figure imgf000148_0003
Formula (l-a"3), Attorney Docket No. 8493-000092/WO/POA
Figure imgf000149_0001
Formula (l-a"10), Formula (l-a"1 1 ),
and
Figure imgf000149_0002
Formula (l-a"12), wherein q is 2, 3, 4, or 5;
Q is a ring atom independently selected from C, N, O, and S, wherein at least one Q is a hetero ring atom selected from N, O and S; Attorney Docket No. 8493-000092/WO/POA
R6 and R7 are independently selected from H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, Ci_io alkanoyloxy, N-(C1-1O alkyl)amino, NN-(C1-1O alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, NN-(C1-1O alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-1O alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-10 alkyl) sulphamoyl and NN-(C1-10 alkyl)2sulphamoyl, or form a 5- or 6-membered cyclic moiety to make a fused ring with the thiazole ring, wherein the cyclic moiety can contain one or more heteroatoms selected from Ν, O and S; wherein each R6 and R7 is optionally substituted by one or more B; and
R6', R7', R8, R9 and R10 are independently selected from H and the functional groups of R5; wherein each R6', R7', R8, R9 and R10 is optionally substituted by one or more D.
15. The compound or pharmaceutically acceptable salt thereof of Claim 14 which is selected from those of Structures (A"0) and (A" 10):
Figure imgf000150_0001
Structure (A11O) and Structure (A"10).
16. The compound of Claim 14 which is selected from the group consisting of:
N-hydroxy-4-(4-(4-(imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide; N-hydroxy-4-(4-(4-(imidazo[l,2-α]pyridin-3-yl)-5-methylthiazol-2-yl)tetrahydropyran-4- yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(imidazo[l,2-α]pyridin-3-yl)-5-methylthiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-hydroxy-4-(4-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-hydroxy-4-(4-(5-methyl-4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide; N-(2-aminophenyl)-4-(4-(5-methyl-4-(2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
4-(4-(4-(6-chloro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(4-(4-(6-chloro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-hydroxy-4-(4-(4-(7-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(7-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide; 4-(4-(4-(7-((dimethylamino)methyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-
4-yl)-/V-hydroxybenzamide;
N-(2-aminophenyl)-4-(4-(4-(7-((dimethylamino)methyl)imidazo[l,2-α]pyridin-3-yl)thiazol-
2-yl)tetrahydropyran-4-yl)benzamide;
N-hydroxy-4-(4-(4-(7-(pyrrolidin-l-ylmethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(7-(pyrrolidin-l-ylmethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-hydroxy-4-(4-(4-(7-(morpholinomethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide; N-(2-aminophenyl)-4-(4-(4-(7-(morpholinomethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-hydroxy-4-(4-(4-(2-methyl-6-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(2-methyl-6-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol- 2-yl)tetrahydropyran-4-yl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-hydroxy-4-(4-(4-(2-methyl-7-(trifluoromethyl)imidazo[l,2-a]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(2-methyl-7-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-
2-yl)tetrahydropyran-4-yl)benzamide; 3-(2-(4-(4-(hydroxycarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-/V-(2- methoxyethyl)-2-methylimidazo[l,2-α]pyridine-7-carboxamide;
3-(2-(4-(4-(2-aminophenylcarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-/V-(2- methoxyethyl)-2-methylimidazo[l,2-α]pyridine-7-carboxamide;
4-(4-(4-(7-cyano-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(4-(4-(7-cyano-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
3-(2-(4-(4-(hydroxycarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-7-carboxamide; 3-(2-(4-(4-(2-aminophenylcarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-2-methyl-N-
(2-morpholinoethyl)imidazo[l,2-α]pyridine-7-carboxamide; methyl 3-(2-(4-(4-(hydroxycarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylate; methyl 3-(2-(4-(4-(2-aminophenylcarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylate;
N-hydroxy-4-(4-(4-(2-methyl-7-(4-methylpiperazine-l-carbonyl)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(2-methyl-7-(4-methylpiperazine-l-carbonyl)imidazo[l,2- α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide; 3-(2-(4-(4-(hydroxycarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylic acid;
3-(2-(4-(4-(2-aminophenylcarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylic acid;
N-hydroxy-4-(4-(4-(2-methyl-7-(2-morpholinoethoxy)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-(2-aminophenyl)-4-(4-(4-(2-methyl-7-(2-morpholinoethoxy)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
4-(4-(4-(7-(2-(dimethylamino)ethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)-./V-hydroxybenzamide; N-(2-aminophenyl)-4-(4-(4-(7-(2-(dimethylamino)ethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
N-hydroxy-4-(4-(4-(7-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(7-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
4-(4-(4-(7-(2-(dimethylamino)ethylamino)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)-./V-hydroxybenzamide;
N-(2-aminophenyl)-4-(4-(4-(7-(2-(dimethylamino)ethylamino)-2-methylimidazo[l,2- α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide; 3-(2-(4-(4-(hydroxycarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-N-(2- methoxyethyl)-2-methylimidazo[l,2-α]pyridine-6-carboxamide;
3-(2-(4-(4-(2-aminophenylcarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-N-(2- methoxyethyl)-2-methylimidazo[l,2-α]pyridine-6-carboxamide;
N-hydroxy-4-(4-(4-(2-methyl-6-(4-methylpiperazine-l-carbonyl)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(2-methyl-6-(4-methylpiperazine-l-carbonyl)imidazo[l,2- α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
3-(2-(4-(4-(hydroxycarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-6-carboxamide; 3-(2-(4-(4-(2-aminophenylcarbamoyl)phenyl)tetrahydropyran-4-yl)thiazol-4-yl)-2-methyl-N-
(2-morpholinoethyl)imidazo[l,2-α]pyridine-6-carboxamide;
N-hydroxy-4-(4-(4-(6-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(6-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-hydroxy-4-(4-(4-(6-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(6-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide; 4-(4-(4-(8-fluoro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(4-(4-(8-fluoro-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
4-(4-(4-(7-((dimethylamino)methyl)-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)-./V-hydroxybenzamide;
N-(2-aminophenyl)-4-(4-(4-(7-((dimethylamino)methyl)-2-methylimidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
4-(4-(4-(6-bromo-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)-N- hydroxybenzamide; N-(2-aminophenyl)-4-(4-(4-(6-bromo-2-methylimidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-hydroxy-4-(4-(4-(7-methoxy-2-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(7-methoxy-2-(trifluoromethyl)imidazo[l,2-α]pyridin-3- yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
N-(2-Amino-phenyl)-4-[4-(4-pyridin-3-yl-thiazol-2-yl)-tetrahydro-pyran-4-yl]-benzamide;
N-(2-Amino-cyclohexa-l,5-dienyl)-4-(4-thiazol-2-yl-tetrahydro-pyran-4-yl)-benzamide;
N-(2-aminophenyl)-4-(4-(4-(6-chloropyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide; N-(2-aminophenyl)-4-(4-(4-(6-(pyrrolidin-l-yl)pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide;
N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridin-2-yl)tetrahydropyran-4-yl)benzamide;
N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-(pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-(2-amino-5-fluorophenyl)-4-(4-(4-(pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(6-(2-methoxyethoxy)pyridin-3-yl)thiazol-2-yl)tetrahydropyran-
4-yl)benzamide; N-(2-aminophenyl)-4-(4-(4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(6,7-dihydropyrano[4,3-d]thiazol-2-yl)tetrahydropyran-4- yl)benzamide;
4-(4-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)tetrahydropyran-4-yl)-N-(2- aminophenyl)benzamide;
4-(4-(5-acetyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)tetrahydropyran-4-yl)-N-(2- amino-5-(thiophen-2-yl)phenyl)benzamide;
N-(2-aminophenyl)-4-(4-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2- yl)tetrahydropyran-4-yl)benzamide; N-(2-amino-5-fluorophenyl)-4-(4-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-(pyrrolidin-l-ylmethyl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-((2-methoxyethoxy)methyl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-(morpholinomethyl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-(6-(4-cyclopropylpiperazin-l-yl)pyridin-3-yl)thiazol-2- yl)tetrahydropyran-4-yl)benzamide; N-(2-aminophenyl)-4-(4-(4-(6-(piperazin-l-yl)pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(4-ethoxythiazol-2-yl)tetrahydropyran-4- yl)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(4-ethoxythiazol-2-yl)tetrahydropyran-4- yl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-(2-aminophenyl)-4-(4-(4-(pyrazin-2-yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
N-hydroxy-4-(4-(4-(pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
,/V-hydroxy-4-(4-(thiazol-2-yl)tetrahydropyran-4-yl)benzamide;
N-hydroxy-4-(4-(4-(6-(4-methylpiperazin-l-yl)pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide;
N-(2-amino-5-(5-chlorothiophen-2-yl)phenyl)-4-(4-(thiazol-2-yl)tetrahydropyran-4- yl)benzamide;
N-(2-amino-5-(5-methylthiophen-2-yl)phenyl)-4-(4-(thiazol-2-yl)tetrahydropyran-4- yl)benzamide; N-(2-aminophenyl)-4-(4-(4-(4-(4-methylpiperazin- 1 -yl)phenyl)thiazol-2-yl)tetrahydropyran-
4-yl)benzamide;
N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(5-(pyridin-3-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide;
W-hydroxy-4-(4-(4-(pyrazin-2-yl)thiazol-2-yl)tetrahydropyran-4-yl)benzamide; N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(4-(pyrazin-2-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide;
N-(2-amino-5-fluorophenyl)-4-(4-(4-(pyrazin-2-yl)thiazol-2-yl)tetrahydropyran-4- yl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(5-(l-hydroxyethyl)-4-methylthiazol-2- yl)tetrahydropyran-4-yl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(4,5-dimethylthiazol-2-yl)tetrahydropyran-4- yl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(5-methylthiazol-2-yl)tetrahydropyran-4- yl)benzamide; and pharmaceutically acceptable salts thereof.
17. The compound or pharmaceutically acceptable salt thereof of Claim 5 which has a formula selected from the group consisting of: Attorney Docket No.8493-000092/WO/POA
Figure imgf000157_0001
(l-b3)
Figure imgf000157_0002
Formula (I b4)
Figure imgf000157_0003
Formula (l-b5)
Figure imgf000157_0004
(l-b6)
Figure imgf000157_0005
Formula (l-b7)
Figure imgf000157_0006
Formula (l-b8)
Figure imgf000157_0007
(l-bθ) Attorney Docket No. 8493-000092/WO/POA
Figure imgf000158_0001
Formula (l-t>10)
Figure imgf000158_0002
and
Figure imgf000158_0003
wherein
R6 and R7 are independently selected from H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, Ci_io alkanoyloxy, N-(C1-1O alkyl)amino, NN-(C1-1O alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, NN-(C1-1O alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-1O alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-10 alkyl) sulphamoyl and NN-(C1-10 alkyl)2sulphamoyl, or form a 5- or 6-membered cyclic moiety to make a fused ring with the thiazole ring, wherein the cyclic moiety can contain one or more heteroatoms selected from Ν, O and S; wherein each R6 and R7 is optionally substituted by one or more B; and
R6', R7', R8, R9 and R10 are independently selected from H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-10 alkyl, C2_i0 alkenyl, C2_i0 alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, NN-(C1-1O alkyl)2amino, C1-1O alkanoylamino, N-(Ci-I0 alkyl)carbamoyl, NN-(C1-1O alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, Ci-io alkoxycarbonyl, NH2-S(O)2NH-, N-(Ci-I0 alkyl) sulphamoyl and NN-(Ci-I0 alkyl)2sulphamoyl, wherein each R6, R7, R8, R9 and R10 is optionally substituted by one or more D.
18. The compound or pharmaceutically acceptable salt thereof of Claim 5 which has a formula selected from the group consisting of: Attorney Docket No. 8493-000092/WO/POA
and
Figure imgf000159_0001
wherein
R6', R7', R8, R9 and R 1 1i0υ are independently selected from H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, N,N-(Ci_io alkyl)2amino, C1-1O alkanoylamino, N-(Ci_io alkyl)carbamoyl, N,N-(Ci_io alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-10 alkoxycarbonyl, NH2-S(O)2NH-, -V-(C1-10 alkyl) sulphamoyl and -V-V-(CM0 alkyl)2sulphamoyl, wherein each R6', R7', R8, R9 and R10 is optionally substituted by one or more D; and
R11, R12, and R13 are independently selected from R4 optionally substituted by one or more B.
19. The compound of Claim 18 which is selected from the group consisting of: Attorney Docket No. 8493-000092/WO/POA
N-hydroxy-4-(l-(4-(imidazo[l,2-α]pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-hydroxy-3-(l-(4-(imidazo[l,2-α]pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(imidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide; N-(2-aminophenyl)-3-(l-(4-(imidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-hydroxy-3-(l-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-3-(l-(4-(2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide; 4-(l-(4-(6-chloro-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(6-chloro-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(7-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
4-(l-(4-(7-((dimethylamino)methyl)imidazo[l,2-α]pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)-
,/V-hydroxybenzamide; N-(2-aminophenyl)-4-(l-(4-(7-((dimethylamino)methyl)imidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(7-(pyrrolidin-l-ylmethyl)imidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(pyrrolidin-l-ylmethyl)imidazo[l,2-α]pyridin-3-yl)pyrimidin- 2-yl)cyclopropyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-hydroxy-4-(l-(4-(7-(morpholinomethyl)imidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(morpholinomethyl)imidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide; N-hydroxy-4-(l-(4-(2-methyl-6-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-6-(trifluoromethyl)imidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(2-methyl-7-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-7-(trifluoromethyl)imidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-N-(2-methoxyethyl)-2- methylimidazo[l,2-α]pyridine-7-carboxamide; 3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-N-(2- methoxyethyl)-2-methylimidazo[l,2-α]pyridine-7-carboxamide;
4-(l-(4-(7-cyano-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-cyano-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-7-carboxamide;
3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-7-carboxamide; methyl 3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylate; methyl 3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylate;
N-hydroxy-4-(l-(4-(2-methyl-7-(4-methylpiperazine-l-carbonyl)imidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
JV-(2-aminophenyl)-4-( 1 -(4-(2-methyl-7-(4-methylpiperazine- 1 -carbonyl)imidazo[ 1 ,2- α]pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-2-methylimidazo[l,2- α]pyridine-7-carboxylic acid; 3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-2- methylimidazo[l,2-α]pyridine-7-carboxylic acid;
N-hydroxy-4-(l-(4-(2-methyl-7-(2-morpholinoethoxy)imidazo[l,2-α]pyridin-3-yl)pyrimidin-
2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-7-(2-morpholinoethoxy)imidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide;
4-(l-(4-(7-(2-(dimethylamino)ethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)-N-hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(2-(dimethylamino)ethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide; N-hydroxy-4-(l-(4-(7-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide;
4-(l-(4-(7-(2-(dimethylamino)ethylamino)-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)-N-hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-(2-(dimethylamino)ethylamino)-2-methylimidazo[l,2- α]pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)benzamide;
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-N-(2-methoxyethyl)-2- methylimidazo[l,2-α]pyridine-6-carboxamide; 3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-N-(2- methoxyethyl)-2-methylimidazo[l,2-α]pyridine-6-carboxamide;
N-hydroxy-4-(l-(4-(2-methyl-6-(4-methylpiperazine-l-carbonyl)imidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(2-methyl-6-(4-methylpiperazine-l-carbonyl)imidazo[l,2- α]pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
3-(2-(l-(4-(hydroxycarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-2-methyl-/V-(2- morpholinoethyl)imidazo[l,2-α]pyridine-6-carboxamide;
3-(2-(l-(4-(2-aminophenylcarbamoyl)phenyl)cyclopropyl)pyrimidin-4-yl)-2-methyl-N-(2- morpholinoethyl)imidazo[l,2-α]pyridine-6-carboxamide; N-hydroxy-4-(l-(4-(6-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(6-(2-methoxyethoxy)-2-methylimidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(6-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(6-methoxy-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
4-(l-(4-(8-fluoro-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)-N- hydroxybenzamide; N-(2-aminophenyl)-4-(l-(4-(8-fluoro-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
4-(l-(4-(7-((dimethylamino)methyl)-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)-N-hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(7-((dimethylamino)methyl)-2-methylimidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide;
4-(l-(4-(6-bromo-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)-N- hydroxybenzamide;
N-(2-aminophenyl)-4-(l-(4-(6-bromo-2-methylimidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide; N-hydroxy-4-(l-(4-(7-methoxy-2-(trifluoromethyl)imidazo[l,2-α]pyridin-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(7-methoxy-2-(trifluoromethyl)imidazo[l,2-α]pyridin-3- yl)pyrimidin-2-yl)cyclopropyl)benzamide; and pharmaceutically acceptable salts thereof. Attorney Docket No. 8493-000092/WO/POA
20. The compound or pharmaceutically acceptable salt thereof of Claim 5 which has a formula selected from the group consisting of:
Figure imgf000164_0001
2) wherein R6', R7', R8, R9 and R10 are independently selected from H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, NN-(C1-1O alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, NN-(C1-1O alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-1O alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-10 alkyl) sulphamoyl and NN-(C1-10 alkyl)2sulphamoyl, wherein each R6, R7, R8, R9 and R10 is optionally substituted by one or more D.
21. The compound of Claim 20 which is selected from the group consisting of: N-hydroxy-4-(l-(4-(l-isopropyl-2-methylimidazol-5-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(l-isopropyl-2-methylimidazol-5-yl)pyrimidin-2- yl)cyclopropyl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-hydroxy-4-(l-(4-(4-isopropyl-5-methyl-l,2,4-triazol-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(4-isopropyl-5-methyl-l,2,4-triazol-3-yl)pyrimidin-2- yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(pyridin-3-yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(pyridin-4-yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(pyridin-4-yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-hydroxy-4-(l-(4-(pyridin-2-yl)pyrimidin-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(l-(4-(pyridin-2-yl)pyrimidin-2-yl)cyclopropyl)benzamide; and pharmaceutically acceptable salts thereof.
22. The compound or pharmaceutically acceptable salt thereof of Claim 5 which has a formula selected from the group consisting of:
(l-d1)
Figure imgf000165_0001
Figure imgf000165_0002
Attorney Docket No. 8493-000092/WO/POA
(l-d7)
Figure imgf000166_0001
Figure imgf000166_0002
and
Figure imgf000166_0003
wherein
R6', R7', R8, R9 and R10are independently selected from H, halo, nitro, cyano, hydroxyl, hydroxyalkyl, haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, N,N-(Ci_io alkyl^amino, C1-1O alkanoylamino, N-(C1- io alkyl)carbamoyl, N,N-(Ci_io alkyl)2carb∑ιmoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, Ci-io alkoxycarbonyl, NH2-S(O)2NH-, N-(C1-10 alkyl) sulphamoyl and N,N-(C1-10 alkyl)2sulphamoyl, wherein each R6', R7', R8, R9 and R10 is optionally substituted by one or more D; and
R11, R12, and R13 are independently selected from R4 optionally substituted by one or more B. Attorney Docket No. 8493-000092/WO/POA
23. The compound of Claim 22 which is selected from the group consisting of: 4-(4-(lH-tetrazol-5-yl)tetrahydropyran-4-yl)-N-(2-amino-5-(thiophen-2- yl)phenyl)benzamide ;
4-(4-(lH-tetrazol-5-yl)tetrahydropyran-4-yl)-N-(4-amino-4'-fluorobiphenyl-3-yl)benzamide; N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(2,3-dihydropyridin-2-yl)tetrahydropyran-4- yl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(pyridin-2-yl)tetrahydropyran-4-yl)benzamide; N-(2-amino-5-(5-chlorothiophen-2-yl)phenyl)-4-(4-(pyridin-2-yl)tetrahydropyran-4- yl)benzamide; and pharmaceutically acceptable salts thereof.
24. The compound or pharmaceutically acceptable salt thereof of Claim 1 selected from those of Formulae (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (M), (I-m), (I-n), (I-o), (I-p), (I-q), and (I-r), and pharmaceutically acceptable salts thereof:
(I-f)
Figure imgf000167_0001
Attorney Docket No. 8493-000092/WO/POA
Figure imgf000168_0001
Attorney Docket No. 8493-000092/WO/POA
Cy1 is C3-7 cycloalkylidene or heterocycloalkylidene;
R1 is hydroxyl, aryl or heteroaryl, wherein aryl or heteroaryl is substituted with -NH2 or -OH at a ring position adjacent to attachment of the -CONH-moiety, and aryl or heteroaryl is optionally further substituted with one or more substituent selected from amino, halo, cyano, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, haloaryl, and haloheterocyclyl, wherein alkyl, alkenyl, or alkynyl is optionally further substituted with one or more groups selected from halo, hydroxyl, alkyl, haloalkyl, cycloalkyl, halophenyl, heterocyclyl, and trialkylsilyl; and each R4 is independently selected from H, halo, nitro, cyano, hydroxyl, hydroxy(Ci_io alkyl), haloalkyl, haloalkoxy, amino, azido, carboxyl, carbamoyl, mercapto, sulphamoyl, C1-1O alkyl, C2-1O alkenyl, C2-1O alkynyl, C1-1O alkoxy, C1-1O alkanoyl, C1-1O alkanoyloxy, N-(C1-1O alkyl)amino, N5N-(C1-1O alkyl)2amino, C1-1O alkanoylamino, N-(C1-1O alkyl)carbamoyl, N5N-
(Ci-10 alkyl)2carbamoyl, C1-1O alkyl-S(O)a wherein a is 0, 1 or 2, C1-1O alkoxycarbonyl,
NH2-S(O)2NH-, N-(Ci_io alkyl) sulphamoyl, -V5JV-(CM0 alkyl)2sulphamoyl, aryl, cycloalkyl and heterocyclyl, wherein if R4 is not aryl, cycloalkyl or heterocyclyl, each R4 is optionally substituted by one or more B, and if R4 is aryl, cycloalkyl or heterocyclyl, R4 is optionally further substituted by one or more R5.
25. The compound of Claim 24 which is selected from the group consisting of: Ν-(2-aminophenyl)-4-(l-(pyridin-2-yl)cyclopropyl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(l-(pyridin-2-yl)cyclopropyl)benzamide;
N-(2-amino-5-(5-chlorothiophen-2-yl)phenyl)-4-(l-(pyridin-2-yl)cyclopropyl)benzamide;
N-(2-aminophenyl)-4-(4-(pyridin-2-yl)tetrahydro-2H-pyran-4-yl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(pyridin-2-yl)tetrahydro-2H-pyran-4-yl)benzamide; N-(2-amino-5-(5-chlorothiophen-2-yl)phenyl)-4-(4-(pyridin-2-yl)tetrahydro-2H-pyran-4- yl)benzamide;
N-(2-aminophenyl)-4-(4-(4,6-bis(2-hydroxypropan-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4- yl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(4,6-bis(2-hydroxypropan-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-yl)benzamide; Attorney Docket No. 8493-000092/WO/POA
N-(2-amino-5-(5-chlorothiophen-2-yl)phenyl)-4-(4-(4,6-bis(2-hydroxypropan-2-yl)pyridin-2- yl)tetrahydro-2H-pyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(2,3-dihydropyridin-2-yl)tetrahydro-2H-pyran-4-yl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(2,3-dihydropyridin-2-yl)tetrahydro-2H-pyran-4- yl)benzamide;
N-(2-amino-5-(thiophen-2-yl)phenyl)-4-(4-(2,3-dihydropyridin-2-yl)tetrahydro-2H-pyran-4- yl)benzamide;
4-(4-(lH-tetrazol-5-yl)tetrahydro-2H-pyran-4-yl)-N-(2-aminophenyl)benzamide;
4-(4-(lH-tetrazol-5-yl)tetrahydro-2H-pyran-4-yl)-N-(4-amino-4'-fluorobiphenyl-3- yl)benzamide;
4-(4-(lH-tetrazol-5-yl)tetrahydro-2H-pyran-4-yl)-N-(2-amino-5-(thiophen-2- yl)phenyl)benzamide ;
N-(2-aminophenyl)-4-(4-(4-(pyrazin-2-yl)-lH-imidazol-2-yl)tetrahydro-2H-pyran-4- yl)benzamide; N-(2-aminophenyl)-4-(4-(l-methyl-4-(pyrazin-2-yl)-lH-imidazol-2-yl)tetrahydro-2H-pyran-
4-yl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(l-methyl-4-(pyrazin-2-yl)-lH-imidazol-2- yl)tetrahydro-2H-pyran-4-yl)benzamide;
N-(2-aminophenyl)-4-(4-(4-phenyl-lH-imidazol-2-yl)tetrahydro-2H-pyran-4-yl)benzamide; N-(2-aminophenyl)-4-(4-(l-methyl-4-phenyl-lH-imidazol-2-yl)tetrahydro-2H-pyran-4- yl)benzamide;
N-(4-amino-4'-fluorobiphenyl-3-yl)-4-(4-(l-methyl-4-phenyl-lH-imidazol-2-yl)tetrahydro-
2H-pyran-4-yl)benzamide;
2-aminophenyl 4-(4-(3-methyl-lH-l,2,4-triazol-5-yl)tetrahydro-2H-pyran-4-yl)benzoate; 4-amino-4'-fluorobiphenyl-3-yl 4-(4-(3-methyl-lH-l,2,4-triazol-5-yl)tetrahydro-2H-pyran-4- yl)benzoate;
2-amino-5-(5-chlorothiophen-2-yl)phenyl 4-(4-(3-methyl-lH-l,2,4-triazol-5-yl)tetrahydro-
2H-pyran-4-yl)benzoate, and pharmaceutically acceptable salts thereof. Attorney Docket No. 8493-000092/WO/POA
26. A pharmaceutical composition comprising an effective amount of one or more compounds according to Claim 1 and a pharmaceutically-acceptable carrier.
27. The pharmaceutical composition according to Claim 26, further comprising one or more anti- cancer agents selected from the group consisting of cyclophosphamide, dacarbazine, cisplatin, methotrexate, mercaptopurine, thioguanine, fluorouracil, cytarabine, vinblastine, paclitaxel, doxorubicin, bleomycin, mitomycin, prednisone, tamoxifen, flutamide, asparaginase, rituximab, trastuzumab, imatinib, retinoic acid, colony- stimulating factor, amifostine, lenalidomide, HDAC inhibitor, CDK inhibitor, camptothecin and topotecan.
28. A method of inhibiting or treating a disease mediated by a histone deacetylase in an animal, comprising administering to said animal a therapeutically effective amount of one or more compounds according to Claim 1.
29. The method according to Claim 28, wherein the disease involves abnormal cell proliferation and/or differentiation.
30. The method according to Claim 28, wherein the disease is selected from the group consisting of a cell proliferative disease, autosomal dominant disorder, genetic related metabolic disorder, fibrosis, autoimmune disease, diabetes, neurological disease, and Alzheimer's disease.
31. The method according to Claim 28, wherein the disease is fibrosis selected from the group consisting of cystic fibrosis, injection fibrosis, endomyocardial fibrosis, pulmonary fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis and renal fibrosis, or cancer selected from the group consisting of bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, skin cancer and thyroid cancer.
PCT/US2009/051964 2008-07-28 2009-07-28 Cycloalkylidene and heterocycloalkylidene histone deacetylase inhibitor compounds WO2010014611A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
NZ590747A NZ590747A (en) 2008-07-28 2009-07-28 Cycloalkylidene and heterocycloalkylidene hdac inhibitor compounds
CN2009801320714A CN102123987A (en) 2008-07-28 2009-07-28 Cycloalkylidene and heterocycloalkylidene histone deacetylase inhibitor compounds
MX2011001090A MX2011001090A (en) 2008-07-28 2009-07-28 Cycloalkylidene and heterocycloalkylidene histone deacetylase inhibitor compounds.
AU2009276699A AU2009276699A1 (en) 2008-07-28 2009-07-28 Cycloalkylidene and heterocycloalkylidene histone deacetylase inhibitor compounds
BRPI0916713A BRPI0916713A2 (en) 2008-07-28 2009-07-28 cycloalkylidene and heterocycloalkylidene histone deacetylase inhibiting compounds
CA2731323A CA2731323A1 (en) 2008-07-28 2009-07-28 Cycloalkylidene and heterocycloalkylidene histone deacetylase inhibitor compounds
EP09790886A EP2326622A1 (en) 2008-07-28 2009-07-28 Cycloalkylidene and heterocycloalkylidene histone deacetylase inhibitor compounds
JP2011521247A JP2011529504A (en) 2008-07-28 2009-07-28 Cycloalkylidene histone deacetylase inhibitor compounds and heterocycloalkylidene histone deacetylase inhibitor compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8408108P 2008-07-28 2008-07-28
US61/084,081 2008-07-28

Publications (1)

Publication Number Publication Date
WO2010014611A1 true WO2010014611A1 (en) 2010-02-04

Family

ID=40996551

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/051964 WO2010014611A1 (en) 2008-07-28 2009-07-28 Cycloalkylidene and heterocycloalkylidene histone deacetylase inhibitor compounds

Country Status (11)

Country Link
US (2) US8088771B2 (en)
EP (1) EP2326622A1 (en)
JP (2) JP2011529504A (en)
KR (1) KR20110038159A (en)
CN (1) CN102123987A (en)
AU (1) AU2009276699A1 (en)
BR (1) BRPI0916713A2 (en)
CA (1) CA2731323A1 (en)
MX (1) MX2011001090A (en)
NZ (1) NZ590747A (en)
WO (1) WO2010014611A1 (en)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
CN102838625A (en) * 2011-06-22 2012-12-26 中国科学院上海药物研究所 Tetrahydropyridothiazole compounds, preparation method, drug compositions containing the same, and uses thereof
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
WO2013010862A1 (en) 2011-07-15 2013-01-24 Basf Se Fungicidal alkyl-substituted 2-[2-chloro-4-(4-chloro-phenoxy)-phenyl]-1-[1,2,4]triazol-1-yl-ethanol compounds
WO2013010894A1 (en) 2011-07-15 2013-01-24 Basf Se Fungicidal phenylalkyl-substituted 2-[2-chloro-4-(4-chloro-phenoxy)-phenyl]-1-[1,2,4]triazol-1-yl-ethanol compounds
WO2013024075A1 (en) 2011-08-15 2013-02-21 Basf Se Fungicidal substituted 1-{2-[2-halo-4-(4-halogen-phenoxy)-phenyl]-2-alkynyloxy-ethyl}-1h-[1,2,4]triazole compounds
WO2013024077A1 (en) 2011-08-15 2013-02-21 Basf Se Fungicidal substituted 1-{2-[2-halo-4-(4-halogen-phenoxy)-phenyl]-2-alkoxy-3-methyl-butyl}-1h-[1,2,4]triazole compounds
WO2013024076A1 (en) 2011-08-15 2013-02-21 Basf Se Fungicidal substituted 1-{2-[2-halo-4-(4-halogen-phenoxy)-phenyl]-2-ethoxy-ethyl}-1h- [1,2,4]triazole compounds
US8420640B2 (en) 2008-08-29 2013-04-16 Treventis Corporation Methods of treating amyloid disease using analogs of 1-(4-nitrophenyl) piperazine
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9265734B2 (en) 2008-09-03 2016-02-23 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US9540395B2 (en) 2011-02-28 2017-01-10 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10029988B2 (en) 2013-03-15 2018-07-24 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10059723B2 (en) 2011-02-28 2018-08-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10660890B2 (en) 2013-10-24 2020-05-26 National Institutes Of Health (Nih), U.S. Dept. Of Health And Human Services (Dhhs), U.S. Government Nih Division Of Extramural Inventions And Technology Resources (Deitr) Treatment of polycystic diseases with an HDAC6 inhibitor

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2690192A1 (en) * 2007-06-26 2008-12-31 Gilead Colorado, Inc. Imidazopyridinyl thiazolyl histone deacetylase inhibitors
TW200922564A (en) * 2007-09-10 2009-06-01 Curis Inc CDK inhibitors containing a zinc binding moiety
BRPI0916713A2 (en) 2008-07-28 2015-11-10 Gilead Science Inc cycloalkylidene and heterocycloalkylidene histone deacetylase inhibiting compounds
AR077975A1 (en) 2009-08-28 2011-10-05 Irm Llc PIRAZOL PYRIMIDINE DERIVATIVES AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
US20120079818A1 (en) * 2010-09-30 2012-04-05 Svihla Gary R Filtration arrangement for an exhaust aftertreatment system for a locomotive two-stroke diesel engine
AU2012335663B2 (en) 2011-11-11 2015-12-24 Array Biopharma Inc. Method of treating a proliferative disease
PL2782557T3 (en) 2011-11-23 2019-03-29 Array Biopharma, Inc. Pharmaceutical formulations
JO3407B1 (en) 2012-05-31 2019-10-20 Eisai R&D Man Co Ltd Tetrahydropyrazolopyrimidine Compounds
ES2670550T3 (en) 2013-10-14 2018-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline derivatives
PT3057964T (en) 2013-10-14 2020-02-25 Eisai R&D Man Co Ltd Selectively substituted quinoline compounds
BR112017009194A2 (en) * 2014-10-31 2017-12-26 Abbvie Sarl substituted tetrahydropyran and method of use
CN110382463B (en) * 2017-01-10 2022-11-04 基石药业（苏州）有限公司 HDAC6 selective inhibitor and preparation method and application thereof
WO2019027855A1 (en) * 2017-08-02 2019-02-07 Merck Sharp & Dohme Corp. Novel substituted phenyl compounds as indoleamine 2,3-dioxygenase (ido) inhibitors
JP7250422B2 (en) * 2017-12-28 2023-04-03 東京応化工業株式会社 Resist composition and resist pattern forming method
AU2019212969A1 (en) * 2018-01-29 2020-08-13 Merck Patent Gmbh GCN2 inhibitors and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092899A1 (en) 2004-03-26 2005-10-06 Methylgene Inc. Inhibitors of histone deacetylase

Family Cites Families (101)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR9707607A (en) 1996-01-16 1999-07-27 Bristol Myers Squibb Co Conformationally restricted aromatic inhibitors of microsomal triflyceride transfer protein and process
US20040006011A1 (en) 1996-07-12 2004-01-08 Gour Barbara J. Peptidomimetic modulators of cell adhesion
US6174905B1 (en) 1996-09-30 2001-01-16 Mitsui Chemicals, Inc. Cell differentiation inducer
US5760246A (en) 1996-12-17 1998-06-02 Biller; Scott A. Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method
US6307049B1 (en) 1998-09-30 2001-10-23 The Procter & Gamble Co. Heterocyclic 2-substituted ketoamides
GB9919778D0 (en) 1999-08-21 1999-10-27 Zeneca Ltd Chemical compounds
WO2001019788A2 (en) 1999-09-17 2001-03-22 Cor Therapeutics, Inc. BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa
WO2001053331A2 (en) 2000-01-24 2001-07-26 Adherex Technologies, Inc. Peptidomimetic modulators of cell adhesion
US20020065303A1 (en) 2000-02-01 2002-05-30 Bing-Yan Zhu Bivalent phenylene inhibitors of factor Xa
US6403588B1 (en) 2000-04-27 2002-06-11 Yamanouchi Pharmaceutical Co., Ltd. Imidazopyridine derivatives
DK1277754T3 (en) 2000-04-27 2005-11-14 Astellas Pharma Inc imidazopyridine
AU2001273040A1 (en) 2000-06-27 2002-01-08 Du Pont Pharmaceuticals Company Factor xa inhibitors
AU2002214626A1 (en) 2000-09-29 2002-04-08 Cor Therapeutics, Inc. Quaternary amines and related inhibitors of factor xa
WO2002034748A1 (en) 2000-10-24 2002-05-02 Sankyo Company, Limited Imidazopyridine derivatives
US7429599B2 (en) 2000-12-06 2008-09-30 Signal Pharmaceuticals, Llc Methods for treating or preventing an inflammatory or metabolic condition or inhibiting JNK
US7129242B2 (en) 2000-12-06 2006-10-31 Signal Pharmaceuticals, Llc Anilinopyrimidine derivatives as JNK pathway inhibitors and compositions and methods related thereto
GB0103926D0 (en) 2001-02-17 2001-04-04 Astrazeneca Ab Chemical compounds
SE0100569D0 (en) 2001-02-20 2001-02-20 Astrazeneca Ab New compounds
KR20030076688A (en) 2001-02-20 2003-09-26 아스트라제네카 아베 2-Arylamino-Pyrimidines for the Treatment of GSK3-Related Disorders
EP1383799A4 (en) 2001-04-10 2008-08-06 Transtech Pharma Inc Probes, systems and methods for drug discovery
EP1401836B1 (en) 2001-06-21 2006-08-23 SmithKline Beecham Corporation Imidazo¬1,2-a|pyridine derivatives for the prophylaxis and treatment of herpes viral infections
WO2003000682A1 (en) 2001-06-25 2003-01-03 Merck & Co., Inc. (pyrimidyl)(phenyl)substituted fused heteroaryl p38 inhibiting and pkg kinase inhibiting compounds
EP1270551A1 (en) 2001-06-26 2003-01-02 Aventis Pharma Deutschland GmbH Urea derivatives with antiproteolytic activity
US7868204B2 (en) 2001-09-14 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
ES2262893T3 (en) 2001-10-05 2006-12-01 Smithkline Beecham Corporation IMIDAZO-PIRIDINE DERIVATIVES FOR USE IN THE TREATMENT OF VIRIC INFECTION BY HERPES.
CA2466115A1 (en) 2001-11-13 2003-05-22 Merck Frosst Canada & Co./Merck Frosst Canada & Cie Cyanoalkylamino derivatives as protease inhibitors
US6995144B2 (en) 2002-03-14 2006-02-07 Eisai Co., Ltd. Nitrogen containing heterocyclic compounds and medicines containing the same
JP2003313126A (en) 2002-04-23 2003-11-06 Sankyo Co Ltd Medicine comprising imidazopyridine derivative as active ingredient
JP2004002826A (en) 2002-04-24 2004-01-08 Sankyo Co Ltd High molecular imidazopyridine derivative
GB0212049D0 (en) 2002-05-24 2002-07-03 Merck Sharp & Dohme Therapeutic agents
US20040034084A1 (en) 2002-05-24 2004-02-19 Celgene Corporation Methods for using JNK inhibitors for treating or preventing disease-related wasting
CA2388358A1 (en) 2002-05-31 2003-11-30 Voiceage Corporation A method and device for multi-rate lattice vector quantization
JP3725105B2 (en) * 2002-08-30 2005-12-07 株式会社東芝 Overdischarge prevention circuit for secondary battery and overdischarge prevention method for secondary battery
UA80296C2 (en) 2002-09-06 2007-09-10 Biogen Inc Imidazolopyridines and methods of making and using the same
JP2006503082A (en) 2002-10-17 2006-01-26 メシルジーン、インコーポレイテッド Inhibitors of histone deacetylase
US20040087642A1 (en) 2002-10-24 2004-05-06 Zeldis Jerome B. Methods of using and compositions comprising a JNK inhibitor for the treatment, prevention, management and/or modification of pain
US20040092568A1 (en) 2002-10-31 2004-05-13 Zeldis Jerome B. Methods for the treatment, prevention and management of macular degeneration
NZ539823A (en) 2002-11-28 2008-04-30 Schering Aktiengessellschaft Chk-, Pdk- and Akt-inhibitory pyrimidines, their production and use as pharmaceutical agents
US20050019366A1 (en) 2002-12-31 2005-01-27 Zeldis Jerome B. Drug-coated stents and methods of use therefor
US7135493B2 (en) * 2003-01-13 2006-11-14 Astellas Pharma Inc. HDAC inhibitor
TW200424174A (en) 2003-02-06 2004-11-16 Hoffmann La Roche New TP diamide
US7208491B2 (en) 2003-02-07 2007-04-24 Hoffmann-La Roche Inc. N-monoacylated o-phenylenediamines
WO2004076452A1 (en) 2003-02-26 2004-09-10 Merck Sharp & Dohme Limited 5,8-DIFLUOROIMIDAZO[1,2-a]PYRIDINES AS GABA-A α2/α3 LIGANDS FOR TREATING ANXIETY AND/OR DEPRESSION
US7320989B2 (en) 2003-02-28 2008-01-22 Encysive Pharmaceuticals, Inc. Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
EP1603900A4 (en) 2003-03-06 2008-08-20 Merck & Co Inc Antiprotozoal imidazopyridine compounds
AU2004230889B2 (en) 2003-04-07 2008-03-13 Pharmacyclics Llc Hydroxamates as therapeutic agents
AU2004230316A1 (en) 2003-04-15 2004-10-28 Pfizer Inc. Alpha substituted carboxylic acid as PPAR modulators
US20050234066A1 (en) 2004-04-15 2005-10-20 Agouron Pharmaceuticals, Inc. Alpha substituted carboxylic acids
US20050187266A1 (en) 2003-04-15 2005-08-25 Pfizer Inc Alpha substituted carboxylic acids
WO2004110350A2 (en) 2003-05-14 2004-12-23 Torreypines Therapeutics, Inc. Compouds and uses thereof in modulating amyloid beta
WO2005006945A2 (en) 2003-07-03 2005-01-27 The Salk Institute For Biological Studies Methods for treating neural disorders and compounds useful therefor
JP4809228B2 (en) 2003-09-24 2011-11-09 メチルジーン インコーポレイテッド Inhibitors of histone deacetylase
EP2609919A3 (en) 2003-09-26 2014-02-26 Exelixis, Inc. c-Met modulators and methods of use
BRPI0416266A (en) 2003-11-06 2007-01-09 Celgene Corp method for treating, preventing and / or controlling an asbestos-related disease or disorder in a patient
US7524851B2 (en) 2003-12-05 2009-04-28 Robert Bosch Gesellschaft Fur Medizinische Forschung (Rbmf) Diagnostic methods for therapeutic compounds and methods for monitoring azathioprine therapy
WO2005060571A2 (en) 2003-12-10 2005-07-07 Merck & Co., Inc. Antiprotozoal imidazopyridine compounds
US7671181B2 (en) 2004-01-16 2010-03-02 Merck Sharp & Dohme Corp. Polynucleotides encoding coccidian parasite casein kinase I, a chemotherapeutic target for antiprotozoal agents
WO2005077368A2 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Treatment of gastro-esophageal reflux disease (gerd)
WO2005077373A2 (en) 2004-02-03 2005-08-25 Astrazeneca Ab Treatment of gastro-esophageal reflux disease (gerd)
DE102004008141A1 (en) 2004-02-19 2005-09-01 Abbott Gmbh & Co. Kg Guanidine compounds and their use as binding partners for 5-HT5 receptors
US20070093492A1 (en) 2004-03-09 2007-04-26 Weir-Torn Jiaang Pyrrolidine derivatives
US7253204B2 (en) 2004-03-26 2007-08-07 Methylgene Inc. Inhibitors of histone deacetylase
WO2005102318A1 (en) 2004-04-20 2005-11-03 Ab Science Use of c-kit inhibitors for treating hiv related diseases
WO2005102325A1 (en) 2004-04-20 2005-11-03 Ab Science Use of c-kit inhibitors for treating inflammatory muscle disorders including myositis and muscular dystrophy
CN1946703A (en) 2004-04-20 2007-04-11 特兰斯泰克制药公司 Substituted thiazole and pyrimidine derivatives as melanocortin receptor modulators
EP1742633A2 (en) 2004-04-23 2007-01-17 AB Science Use of c-kit inhibitors for treating fibrosis
WO2005102326A2 (en) 2004-04-23 2005-11-03 Ab Science Use of c-kit inhibitors for treating renal diseases
WO2005102455A1 (en) 2004-04-23 2005-11-03 Ab Science Use of c-kit inhibitors for treating plasmodium related diseases
TW200613307A (en) * 2004-05-17 2006-05-01 Tibotec Pharm Ltd 4-substituted-1,5-dihydro-pyrido[3,2-b]indol-2-ones
CA2566104A1 (en) 2004-05-18 2005-12-01 Ab Science Use of mast cells inhibitors for treating patients exposed to chemical or biological weapons
WO2005115304A2 (en) 2004-05-24 2005-12-08 Ab Science Use of c-kit inhibitors for treating fibrodysplasia
WO2005115385A1 (en) 2004-05-24 2005-12-08 Ab Science Use of c-kit inhibitors for treating acne
PL1781639T3 (en) 2004-07-28 2012-07-31 Janssen Pharmaceutica Nv Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase
WO2006038001A1 (en) 2004-10-06 2006-04-13 Celltech R & D Limited Aminopyrimidine derivatives as jnk inhibitors
WO2006044509A2 (en) 2004-10-15 2006-04-27 Biogen Idec Ma Inc. Methods of treating vascular injuries
ZA200704889B (en) 2004-11-23 2008-09-25 Celgene Corp JNK inhibitors for treatment of CNS injury
CN101098698A (en) 2004-12-01 2008-01-02 德福根有限公司 5-carboxamido substitued thiazole derivatives that interact with ion channels, in particular with ion channels from the kv family
CA2589793A1 (en) 2004-12-17 2006-06-22 Astrazeneca Ab 4-(4-(imidazol-4-yl)pyrimidin-2-ylamino) benzamides as cdk inhibitors
US20080167314A1 (en) 2004-12-28 2008-07-10 Osamu Uchikawa Condensed Imidazole Compound And Use Thereof
JP2008527031A (en) 2005-01-19 2008-07-24 バイオリポックス エービー Pyrrolopyridine derivatives useful for the treatment of inflammation
AU2006223508A1 (en) * 2005-03-09 2006-09-21 Merck Frosst Canada Ltd Diphenyl substituted cycloalkanes, compositions containing such compounds and methods of use
US20060223807A1 (en) 2005-03-29 2006-10-05 University Of Massachusetts Medical School, A Massachusetts Corporation Therapeutic methods for type I diabetes
WO2006108059A1 (en) 2005-04-06 2006-10-12 Exelixis, Inc. C-met modulators and methods of use
EP1879575A2 (en) 2005-05-09 2008-01-23 Achillion Pharmaceuticals, Inc. Thiazole compounds and methods of use
JP4528918B2 (en) 2005-06-21 2010-08-25 学校法人 関西大学 Carboxamide derivatives
BRPI0612124A2 (en) 2005-06-24 2010-10-19 Genelabs Tech Inc heteroaryl derivatives for the treatment of viruses
US7309787B2 (en) 2005-07-13 2007-12-18 Allergan, Inc. Kinase inhibitors
EP1904065A2 (en) 2005-07-14 2008-04-02 AB Science Use of dual c-kit/fgfr3 inhibitors for treating multiple myeloma
EA200800755A1 (en) 2005-09-07 2008-10-30 Лаборатуар Сероно С.А. IKK INHIBITORS INTRODUCED FOR THE TREATMENT OF ENDOMETRIOSIS
BRPI0616574A2 (en) 2005-09-27 2009-11-24 Shionogi & Co sulfonamide derivative having pgd2 receptor antagonistic activity
KR20080049130A (en) 2005-09-30 2008-06-03 아스트라제네카 아베 Imidazo [1,2-a] pyridine having anti-cell-proliferation activity
UY29827A1 (en) 2005-10-03 2007-05-31 Astrazeneca Ab 2-AMINA-PYRIMIDINE-4- (2-METHYL-1- (TETRAHIDRO-2H-PIRAN-4-IL) -1-IMIDAZOL-5-Y1) SUBSTITUTED AND ITS DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, PROCESSES FOR PREPARATION AND APPLICATIONS
ITMI20060296A1 (en) 2006-02-17 2007-08-18 Alberto Lodolo MULTIFUNCTIONAL INTERCEPTION DEVICE
EP1996233A2 (en) 2006-02-27 2008-12-03 Gilead Colorado, Inc. Combinations comprising a histone deacetylase inhibiting agent and a nuclear hormone receptor ligand for treating cardiovascular conditions
US8119685B2 (en) 2006-04-26 2012-02-21 Merck Sharp & Dohme Corp. Disubstituted aniline compounds
CA2690192A1 (en) 2007-06-26 2008-12-31 Gilead Colorado, Inc. Imidazopyridinyl thiazolyl histone deacetylase inhibitors
AU2009271003A1 (en) 2008-07-14 2010-01-21 Gilead Sciences, Inc. Imidazolylpyrimidine compounds as HDAC and/or CDK inhibitors
NZ602832A (en) 2008-07-14 2014-04-30 Gilead Sciences Inc Fused heterocyclic hdac inhibitor compounds
BRPI0916713A2 (en) 2008-07-28 2015-11-10 Gilead Science Inc cycloalkylidene and heterocycloalkylidene histone deacetylase inhibiting compounds
EP2440519A1 (en) 2009-06-08 2012-04-18 Gilead Sciences, Inc. Alkanoylamino benzamide aniline hdac inihibitor compounds
AU2010259042A1 (en) 2009-06-08 2011-12-15 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092899A1 (en) 2004-03-26 2005-10-06 Methylgene Inc. Inhibitors of histone deacetylase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MORADEI ET AL.: "Histone Deacetylase Inhibitors: Latest Developments, Trends, and Prospects", CURR. MED. CHEM.: ANTI-CANCER AGENTS, vol. 5, no. 5, 2005, pages 529 - 560

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8420640B2 (en) 2008-08-29 2013-04-16 Treventis Corporation Methods of treating amyloid disease using analogs of 1-(4-nitrophenyl) piperazine
US9796664B2 (en) 2008-09-03 2017-10-24 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US9265734B2 (en) 2008-09-03 2016-02-23 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10301323B2 (en) 2011-02-28 2019-05-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10280182B2 (en) 2011-02-28 2019-05-07 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10526346B2 (en) 2011-02-28 2020-01-07 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10059723B2 (en) 2011-02-28 2018-08-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10981933B2 (en) 2011-02-28 2021-04-20 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9512143B2 (en) 2011-02-28 2016-12-06 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9540395B2 (en) 2011-02-28 2017-01-10 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9908899B2 (en) 2011-02-28 2018-03-06 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
CN102838625A (en) * 2011-06-22 2012-12-26 中国科学院上海药物研究所 Tetrahydropyridothiazole compounds, preparation method, drug compositions containing the same, and uses thereof
WO2013010862A1 (en) 2011-07-15 2013-01-24 Basf Se Fungicidal alkyl-substituted 2-[2-chloro-4-(4-chloro-phenoxy)-phenyl]-1-[1,2,4]triazol-1-yl-ethanol compounds
WO2013010894A1 (en) 2011-07-15 2013-01-24 Basf Se Fungicidal phenylalkyl-substituted 2-[2-chloro-4-(4-chloro-phenoxy)-phenyl]-1-[1,2,4]triazol-1-yl-ethanol compounds
WO2013024076A1 (en) 2011-08-15 2013-02-21 Basf Se Fungicidal substituted 1-{2-[2-halo-4-(4-halogen-phenoxy)-phenyl]-2-ethoxy-ethyl}-1h- [1,2,4]triazole compounds
WO2013024077A1 (en) 2011-08-15 2013-02-21 Basf Se Fungicidal substituted 1-{2-[2-halo-4-(4-halogen-phenoxy)-phenyl]-2-alkoxy-3-methyl-butyl}-1h-[1,2,4]triazole compounds
WO2013024075A1 (en) 2011-08-15 2013-02-21 Basf Se Fungicidal substituted 1-{2-[2-halo-4-(4-halogen-phenoxy)-phenyl]-2-alkynyloxy-ethyl}-1h-[1,2,4]triazole compounds
US10029988B2 (en) 2013-03-15 2018-07-24 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10428028B2 (en) 2013-03-15 2019-10-01 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10660890B2 (en) 2013-10-24 2020-05-26 National Institutes Of Health (Nih), U.S. Dept. Of Health And Human Services (Dhhs), U.S. Government Nih Division Of Extramural Inventions And Technology Resources (Deitr) Treatment of polycystic diseases with an HDAC6 inhibitor
US11666569B2 (en) 2013-10-24 2023-06-06 National Institutes Of Health (Nih), U.S. Dept. Of Health And Human Services (Dhhs) U.S. Government Treatment of polycystic diseases with an HDAC6 inhibitor

Also Published As

Publication number Publication date
EP2326622A1 (en) 2011-06-01
CA2731323A1 (en) 2010-02-04
US8088771B2 (en) 2012-01-03
NZ590747A (en) 2012-11-30
BRPI0916713A2 (en) 2015-11-10
JP2011529504A (en) 2011-12-08
US20100022543A1 (en) 2010-01-28
CN102123987A (en) 2011-07-13
MX2011001090A (en) 2011-03-15
US8198299B2 (en) 2012-06-12
AU2009276699A1 (en) 2010-02-04
KR20110038159A (en) 2011-04-13
JP2014098002A (en) 2014-05-29
US20120045412A1 (en) 2012-02-23

Similar Documents

Publication Publication Date Title
US8198299B2 (en) Cycloalkylidene and heterocycloalkylidene inhibitor compounds
JP5640006B2 (en) Condensed heterocyclic inhibitors of histone deacetylases and / or cyclin-dependent kinases
JP5640005B2 (en) Imidazosylpyridine compounds as HDAC and / or CDK inhibitors
US20090005374A1 (en) Imidazopyridinyl thiazolyl histone deacetylase inhibitors
WO2016147659A1 (en) Bicyclic imidazolo derivative
AU2010259042A1 (en) Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US20120040998A1 (en) 2-alkyl piperidine mglur5 receptor modulators
CA2637198A1 (en) Hydantoin compounds for the treatment of inflammatory disorders
WO2010009166A1 (en) Oxindolyl inhibitor compounds
WO2009023193A1 (en) Certain chemical entities, compositions, and methods
WO2007056078A2 (en) Certain chemical entities, compositions, and methods
AU2009316790A1 (en) Inhibitors of diacylglycerol acyltransferase
AU2008282032A1 (en) Novel heterocyclic compounds as mGlu5 antagonists
JP2022521536A (en) Imidazopyridinyl compounds and their use for the treatment of neurodegenerative disorders

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200980132071.4

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09790886

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2731323

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2009276699

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 544/DELNP/2011

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2009790886

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2011521247

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 590747

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: MX/A/2011/001090

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2009276699

Country of ref document: AU

Date of ref document: 20090728

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20117004842

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: PI0916713

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20110127